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Circadian Rhythms in Liver Physiology and Liver Diseases

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Abstract

In mammals, circadian rhythms function to coordinate a diverse panel of physiological processes with environmental conditions such as food and light. As the driving force for circadian rhythmicity, the molecular clock is a self‐sustained transcription‐translational feedback loop system consisting of transcription factors, epigenetic modulators, kinases/phosphatases, and ubiquitin E3 ligases. The molecular clock exists not only in the suprachiasmatic nuclei of the hypothalamus but also in the peripheral tissues to regulate cellular and physiological function in a tissue‐specific manner. The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Clock gene mutant animals display impaired glucose and lipid metabolism and are susceptible to diet‐induced obesity and metabolic dysfunction, providing strong evidence for the connection between the circadian clock and metabolic homeostasis. Circadian‐controlled hepatic metabolism is partially achieved by controlling the expression and/or activity of key metabolic enzymes, transcription factors, signaling molecules, and transporters. Reciprocally, intracellular metabolites modulate the molecular clock activity in response to the energy status. Although still at the early stage, circadian clock dysfunction has been implicated in common chronic liver diseases. Circadian dysregulation of lipid metabolism, detoxification, reactive oxygen species (ROS) production, and cell‐cycle control might contribute to the onset and progression of liver steatosis, fibrosis, and even carcinogenesis. In summary, these findings call for a comprehensive study of the function and mechanisms of hepatic circadian clock to gain better understanding of liver physiology and diseases. © 2013 American Physiological Society. Compr Physiol 3:917‐940, 2013.

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Figure 1. Figure 1.

Daily entrainment signals of the central and peripheral circadian clocks. Light is the dominant signal to reset the central circadian clock located in the suprachiasmatic nucleaus (SCN) via the retino‐hypothalamus tract. Following resetting, the SCN dictates rhythms of locomotor activity, sleep‐wake cycle, blood pressure, and body temperature. In parallel, the SCN entrains the peripheral clock tissues via direct humoral factors or autonomic innervations. The major peripheral clock tissues associated with metabolism include the liver, adipose tissues, skeletal muscle, pancreas, and adrenal glands. The synchronized activities of peripheral clock tissues are required for maintaining metabolic homeostasis and balancing energy utilization. Food and feeding regimen reset the peripheral clock tissues without affecting the SCN.

Figure 2. Figure 2.

The molecular clock network is driven by a transcription‐translational feedback mechanism. The primary molecular oscillator is composed of the primary positive loop (CLOCK/NAPS2 and BMAL1) and the primary negative loop (PERs and CRYs). BMAL1:CLOCK transcription complex binds to E‐box sequences located in the promoter of Per and Cry genes to activate their transcription. PER and CRY proteins are necessary components of the feedback inhibition of BMAL1:CLOCK transcription complex. Once accumulated in the cytosol, PER and CRY proteins undergo dimerization, nuclear translocation to inhibit their own gene transcription by BMAL1: CLOCK complex. Both PER and CRY are targets of phosphorylation and ubiquitination‐mediated proteasome degradation. BMAL1:CLOCK is also required for activation of nuclear receptors NR1D1/2 and ROR, which constitutes the secondary circadian feedback loop. NR1D1/2 represses Bmal1 transcription and competes with ROR for binding to RRE (ROR response element) within the Bmal1 promoter. The maximal repression of NR1D1 is achieved via recruitment of corepressor complex NCoR‐HDAC3 in a heme‐dependent manner. BMAL1:CLOCK also participates E‐box dependent rhythmic expression of circadian controlled genes (CCGs). NR1D1 and NR1D2 also contribute to rhythmic expression of CCGs via a RRE‐dependent manner.

Figure 3. Figure 3.

Regulation of the molecular clock by the intracellular energy state. (A) The role of nicotinamide adenosine dinucleotide (NAD)/NAD(P)H levels in regulation of the molecular clock. High levels of NAD(P)H enhances BMAL1:CLOCK binding to targeted DNA. CLOCK with intrinsic HAT activity catalyzes BMAL1 acetylation and in turn activates transcription of Cry (s) and Per(s) and circadian‐controlled gene Nampt, a key enzyme for NAD biosynthesis. When NAD level rises during each circadian cycle, NAD stimulates SIRT1 enzymatic activity, which in turn deacetylates PER protein for proteasome degradation. SIRT1 also deacetylates BMAL1 and releases the repression of CRY:PER on BMAL1:CLOCK transcription activity. (B) The role adenosine monophosphate/adenosine triphosphate (AMP/ATP) levels in regulation of the molecular clock. High level of AMP activates AMPK, a cellular sensor for lower energy state. AMPK inhibits negative feedback loop via its activation of SIRT1 and phosphorylation CRY protein. AMPK‐dependent phosphorylation of CRY promotes its ubiquitianation and proteasome‐mediated degradation. In addition, AMPK enhances PER2 degradation by promoting the kinase activity of CKI ɛ/δ.

Figure 4. Figure 4.

The physiology and potential disease relevance of hepatic liver clock. The circadian network within the hepatocyte shares the same molecular structure with that found in the SCN. BMAL1:CLOCK activates the expression of Per and Cry while PER:CRY repress their own transcription via inhibiting BMAL1:CLOCK. The hepatic circadian clock can be entrained or phase shifted by a variety of hormones (insulin, glucagons, and glucocorticoid), nutrients (glucose, fatty acid, and bile acid) and environmental chemicals (Dioxin). Specific input signaling resets or shifts the molecular clock, subsequently affecting its output pathways, including nutrient metabolic pathways, xenobiotic metabolism, and cell‐cycle regulation. Impaired circadian clock might be an underlying mechanism for chronic liver diseases.



Figure 1.

Daily entrainment signals of the central and peripheral circadian clocks. Light is the dominant signal to reset the central circadian clock located in the suprachiasmatic nucleaus (SCN) via the retino‐hypothalamus tract. Following resetting, the SCN dictates rhythms of locomotor activity, sleep‐wake cycle, blood pressure, and body temperature. In parallel, the SCN entrains the peripheral clock tissues via direct humoral factors or autonomic innervations. The major peripheral clock tissues associated with metabolism include the liver, adipose tissues, skeletal muscle, pancreas, and adrenal glands. The synchronized activities of peripheral clock tissues are required for maintaining metabolic homeostasis and balancing energy utilization. Food and feeding regimen reset the peripheral clock tissues without affecting the SCN.



Figure 2.

The molecular clock network is driven by a transcription‐translational feedback mechanism. The primary molecular oscillator is composed of the primary positive loop (CLOCK/NAPS2 and BMAL1) and the primary negative loop (PERs and CRYs). BMAL1:CLOCK transcription complex binds to E‐box sequences located in the promoter of Per and Cry genes to activate their transcription. PER and CRY proteins are necessary components of the feedback inhibition of BMAL1:CLOCK transcription complex. Once accumulated in the cytosol, PER and CRY proteins undergo dimerization, nuclear translocation to inhibit their own gene transcription by BMAL1: CLOCK complex. Both PER and CRY are targets of phosphorylation and ubiquitination‐mediated proteasome degradation. BMAL1:CLOCK is also required for activation of nuclear receptors NR1D1/2 and ROR, which constitutes the secondary circadian feedback loop. NR1D1/2 represses Bmal1 transcription and competes with ROR for binding to RRE (ROR response element) within the Bmal1 promoter. The maximal repression of NR1D1 is achieved via recruitment of corepressor complex NCoR‐HDAC3 in a heme‐dependent manner. BMAL1:CLOCK also participates E‐box dependent rhythmic expression of circadian controlled genes (CCGs). NR1D1 and NR1D2 also contribute to rhythmic expression of CCGs via a RRE‐dependent manner.



Figure 3.

Regulation of the molecular clock by the intracellular energy state. (A) The role of nicotinamide adenosine dinucleotide (NAD)/NAD(P)H levels in regulation of the molecular clock. High levels of NAD(P)H enhances BMAL1:CLOCK binding to targeted DNA. CLOCK with intrinsic HAT activity catalyzes BMAL1 acetylation and in turn activates transcription of Cry (s) and Per(s) and circadian‐controlled gene Nampt, a key enzyme for NAD biosynthesis. When NAD level rises during each circadian cycle, NAD stimulates SIRT1 enzymatic activity, which in turn deacetylates PER protein for proteasome degradation. SIRT1 also deacetylates BMAL1 and releases the repression of CRY:PER on BMAL1:CLOCK transcription activity. (B) The role adenosine monophosphate/adenosine triphosphate (AMP/ATP) levels in regulation of the molecular clock. High level of AMP activates AMPK, a cellular sensor for lower energy state. AMPK inhibits negative feedback loop via its activation of SIRT1 and phosphorylation CRY protein. AMPK‐dependent phosphorylation of CRY promotes its ubiquitianation and proteasome‐mediated degradation. In addition, AMPK enhances PER2 degradation by promoting the kinase activity of CKI ɛ/δ.



Figure 4.

The physiology and potential disease relevance of hepatic liver clock. The circadian network within the hepatocyte shares the same molecular structure with that found in the SCN. BMAL1:CLOCK activates the expression of Per and Cry while PER:CRY repress their own transcription via inhibiting BMAL1:CLOCK. The hepatic circadian clock can be entrained or phase shifted by a variety of hormones (insulin, glucagons, and glucocorticoid), nutrients (glucose, fatty acid, and bile acid) and environmental chemicals (Dioxin). Specific input signaling resets or shifts the molecular clock, subsequently affecting its output pathways, including nutrient metabolic pathways, xenobiotic metabolism, and cell‐cycle regulation. Impaired circadian clock might be an underlying mechanism for chronic liver diseases.

References
 1. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am 91: 1125‐1149, ix, 2007.
 2. Abe M, Herzog ED, Block GD. Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport 11: 3261‐3264, 2000.
 3. Acimovic J, Fink M, Pompon D, Bjorkhem I, Hirayama J, Sassone‐Corsi P, Golicnik M, Rozman D. CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochem Biophys Res Commun 376: 206‐210, 2008.
 4. Akiyama TE, Meinke PT, Berger JP. PPAR ligands: Potential therapies for metabolic syndrome. Curr Diab Rep 5: 45‐52, 2005.
 5. Albrecht U, Zheng B, Larkin D, Sun ZS, Lee CC. MPer1 and mper2 are essential for normal resetting of the circadian clock. J Biol Rhythms 16: 100‐104, 2001.
 6. Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji‐Adele A, Avila J, Bucan M, Ahima RS, Kaestner KH, Lazar MA. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456: 997‐1000, 2008.
 7. Altamirano J, Bataller R. Alcoholic liver disease: Pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol 8: 491‐501, 2011.
 8. Ando H, Oshima Y, Yanagihara H, Hayashi Y, Takamura T, Kaneko S, Fujimura A. Profile of rhythmic gene expression in the livers of obese diabetic KK‐A(y) mice. Biochem Biophys Res Commun 346: 1297‐1302, 2006.
 9. Ando H, Takamura T, Matsuzawa‐Nagata N, Shima KR, Eto T, Misu H, Shiramoto M, Tsuru T, Irie S, Fujimura A, Kaneko S. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia 52: 329‐335, 2009.
 10. Ando H, Takamura T, Matsuzawa‐Nagata N, Shima KR, Nakamura S, Kumazaki M, Kurita S, Misu H, Togawa N, Fukushima T, Fujimura A, Kaneko S. The hepatic circadian clock is preserved in a lipid‐induced mouse model of non‐alcoholic steatohepatitis. Biochem Biophys Res Commun 380: 684‐688, 2009.
 11. Ando H, Ushijima K, Yanagihara H, Hayashi Y, Takamura T, Kaneko S, Fujimura A. Clock gene expression in the liver and adipose tissues of non‐obese type 2 diabetic Goto‐Kakizaki rats. Clin Exp Hypertens 31: 201‐207, 2009.
 12. Arble DM, Bass J, Laposky AD, Vitaterna MH, Turek FW. Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring) 17: 2100‐2102, 2009.
 13. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317‐328, 2008.
 14. Asher G, Reinke H, Altmeyer M, Gutierrez‐Arcelus M, Hottiger MO, Schibler U. Poly(ADP‐ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. Cell 142: 943‐953, 2010.
 15. Asher G, Schibler U. Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab 13: 125‐137, 2011.
 16. Atkinson SE, Maywood ES, Chesham JE, Wozny C, Colwell CS, Hastings MH, Williams SR. Cyclic AMP signaling control of action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus. J Biol Rhythms 26: 210‐220, 2011.
 17. Auwerx J, Schoonjans K, Fruchart JC, Staels B. Transcriptional control of triglyceride metabolism: Fibrates and fatty acids change the expression of the LPL and apo C‐III genes by activating the nuclear receptor PPAR. Atherosclerosis 124 (Suppl): S29‐S37, 1996.
 18. Bae Y, Kemper JK, Kemper B. Repression of CAR‐mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol 23: 81‐91, 2004.
 19. Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289: 2344‐2347, 2000.
 20. Balsalobre A, Marcacci L, Schibler U. Multiple signaling pathways elicit circadian gene expression in cultured Rat‐1 fibroblasts. Curr Biol 10: 1291‐1294, 2000.
 21. Berger JP, Akiyama TE, Meinke PT. PPARs: Therapeutic targets for metabolic disease. Trends Pharmacol Sci 26: 244‐251, 2005.
 22. Bertolucci C, Cavallari N, Colognesi I, Aguzzi J, Chen Z, Caruso P, Foa A, Tosini G, Bernardi F, Pinotti M. Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators. Mol Cell Biol 28: 3070‐3075, 2008.
 23. Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: A comprehensive review. Pediatr Dev Pathol 7: 315‐334, 2004.
 24. Brewer M, Lange D, Baler R, Anzulovich A. SREBP‐1 as a transcriptional integrator of circadian and nutritional cues in the liver. J Biol Rhythms 20: 195‐205, 2005.
 25. Brown JD, Plutzky J. Peroxisome proliferator‐activated receptors as transcriptional nodal points and therapeutic targets. Circulation 115: 518‐533, 2007.
 26. Brown SA, Ripperger J, Kadener S, Fleury‐Olela F, Vilbois F, Rosbash M, Schibler U. PERIOD1‐associated proteins modulate the negative limb of the mammalian circadian oscillator. Science 308: 693‐696, 2005.
 27. Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, Jager J, Lazar MA. Rev‐erbalpha and Rev‐erbbeta coordinately protect the circadian clock and normal metabolic function. Genes Dev 26: 657‐667.
 28. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009‐1017, 2000.
 29. Burioka N, Fukuoka Y, Takata M, Endo M, Miyata M, Chikumi H, Tomita K, Kodani M, Touge H, Takeda K, Sumikawa T, Yamaguchi K, Ueda Y, Nakazaki H, Suyama H, Yamasaki A, Sano H, Igishi T, Shimizu E. Circadian rhythms in the CNS and peripheral clock disorders: Function of clock genes: Influence of medication for bronchial asthma on circadian gene. J Pharmacol Sci 103: 144‐149, 2007.
 30. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316: 900‐904, 2007.
 31. Campos‐de‐Sousa S, Guindalini C, Tondo L, Munro J, Osborne S, Floris G, Pedrazzoli M, Tufik S, Breen G, Collier D. Nuclear receptor rev‐erb‐{alpha} circadian gene variants and lithium carbonate prophylaxis in bipolar affective disorder. J Biol Rhythms 25: 132‐137, 2010.
 32. Canaple L, Rambaud J, Dkhissi‐Benyahya O, Rayet B, Tan NS, Michalik L, Delaunay F, Wahli W, Laudet V. Reciprocal regulation of brain and muscle Arnt‐like protein 1 and peroxisome proliferator‐activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock. Mol Endocrinol 20: 1715‐1727, 2006.
 33. Canto C, Auwerx J. PGC‐1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20: 98‐105, 2009.
 34. Canto C, Auwerx J. AMP‐activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci 67: 3407‐3423, 2010.
 35. Canto C, Gerhart‐Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056‐1060, 2009.
 36. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11: 213‐219, 2010.
 37. Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone‐Corsi P. Circadian clock control by SUMOylation of BMAL1. Science 309: 1390‐1394, 2005.
 38. Cella LK, Van Cauter E, Schoeller DA. Effect of meal timing on diurnal rhythm of human cholesterol synthesis. Am J Physiol 269: E878‐883, 1995.
 39. Challet E, Mendoza J. Metabolic and reward feeding synchronises the rhythmic brain. Cell Tissue Res 341: 1‐11.
 40. Chen C, Williams PF, Cooney GJ, Caterson ID. Diurnal rhythms of glycogen metabolism in the liver and skeletal muscle in gold thioglucose induced‐obese mice with developing insulin resistance. Int J Obes Relat Metab Disord 16: 913‐921, 1992.
 41. Chen CP, Kuhn P, Advis JP, Sarkar DK. Prenatal ethanol exposure alters the expression of period genes governing the circadian function of beta‐endorphin neurons in the hypothalamus. J Neurochem 97: 1026‐1033, 2006.
 42. Chen P, Han Z, Yang P, Zhu L, Hua Z, Zhang J. Loss of clock gene mPer2 promotes liver fibrosis induced by carbon tetrachloride. Hepatol Res 40: 1117‐1127.
 43. Chen P, Kakan X, Wang S, Dong W, Jia A, Cai C, Zhang J. Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice. Exp Toxicol Pathol.
 44. Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, Weaver DR, Leslie FM, Zhou QY. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417: 405‐410, 2002.
 45. Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis 28: 351‐359, 2008.
 46. Cheung O, Sanyal AJ. Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol 26: 202‐208, 2010.
 47. Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, DiTacchio L, Atkins AR, Glass CK, Liddle C, Auwerx J, Downes M, Panda S, Evans RM. Regulation of circadian behaviour and metabolism by REV‐ERB‐alpha and REV‐ERB‐beta. Nature 485: 123‐127, 2012.
 48. Cho Y, Noshiro M, Choi M, Morita K, Kawamoto T, Fujimoto K, Kato Y, Makishima M. The basic helix‐loop‐helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. Mol Pharmacol 76: 1360‐1369, 2009.
 49. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 122: 1649‐1657, 2002.
 50. Colwell CS. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 12: 553‐569, 2011.
 51. Correia MA, Sinclair PR, De Matteis F. Cytochrome P450 regulation: The interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal. Drug Metab Rev 43: 1‐26, 2010.
 52. Cretenet G, Le Clech M, Gachon F. Circadian clock‐coordinated 12 Hr period rhythmic activation of the IRE1alpha pathway controls lipid metabolism in mouse liver. Cell Metab 11: 47‐57.
 53. Crumbley C, Burris TP. Direct regulation of CLOCK expression by REV‐ERB. PLoS One 6: e17290, 2011.
 54. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury‐Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14: 2950‐2961, 2000.
 55. Davidson AJ, Straume M, Block GD, Menaker M. Daily timed meals dissociate circadian rhythms in hepatoma and healthy host liver. Int J Cancer 118: 1623‐1627, 2006.
 56. Davis S, Mirick DK. Circadian disruption, shift work and the risk of cancer: A summary of the evidence and studies in Seattle. Cancer Causes Control 17: 539‐545, 2006.
 57. Debruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM. A clock shock: Mouse CLOCK is not required for circadian oscillator function. Neuron 50: 465‐477, 2006.
 58. Decaux JF, Antoine B, Kahn A. Regulation of the expression of the L‐type pyruvate kinase gene in adult rat hepatocytes in primary culture. J Biol Chem 264: 11584‐11590, 1989.
 59. DeLeve LD, Jaeschke H, Kalra VK, Asahina K, Brenner DA, Tsukamoto H. 15th International Symposium on Cells of the Hepatic Sinusoid, 2010. Liver Int 31: 762‐772.
 60. Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C. ChREBP, but not LXRs, is required for the induction of glucose‐regulated genes in mouse liver. J Clin Invest 118: 956‐964, 2008.
 61. Diehl AM. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol 282: G1‐5, 2002.
 62. DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S. Histone lysine demethylase JARID1a activates CLOCK‐BMAL1 and influences the circadian clock. Science 333: 1881‐1885, 2011.
 63. Doi M, Hirayama J, Sassone‐Corsi P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125: 497‐508, 2006.
 64. Doi R, Oishi K, Ishida N. CLOCK regulates circadian rhythms of hepatic glycogen synthesis through transcriptional activation of Gys2. J Biol Chem 285: 22114‐22121, 2010.
 65. Dooley S, ten Dijke P. TGF‐beta in progression of liver disease. Cell Tissue Res 347: 245‐256.
 66. Drucker‐Colin R, Aguilar‐Roblero R, Garcia‐Hernandez F, Fernandez‐Cancino F, Bermudez Rattoni F. Fetal suprachiasmatic nucleus transplants: Diurnal rhythm recovery of lesioned rats. Brain Res 311: 353‐357, 1984.
 67. Dudley CA, Erbel‐Sieler C, Estill SJ, Reick M, Franken P, Pitts S, McKnight SL. Altered patterns of sleep and behavioral adaptability in NPAS2‐deficient mice. Science 301: 379‐383, 2003.
 68. Duez H, Lefebvre B, Poulain P, Torra IP, Percevault F, Luc G, Peters JM, Gonzalez FJ, Gineste R, Helleboid S, Dzavik V, Fruchart JC, Fievet C, Lefebvre P, Staels B. Regulation of human apoA‐I by gemfibrozil and fenofibrate through selective peroxisome proliferator‐activated receptor alpha modulation. Arterioscler Thromb Vasc Biol 25: 585‐591, 2005.
 69. Duez H, van der Veen JN, Duhem C, Pourcet B, Touvier T, Fontaine C, Derudas B, Bauge E, Havinga R, Bloks VW, Wolters H, van der Sluijs FH, Vennstrom B, Kuipers F, Staels B. Regulation of bile acid synthesis by the nuclear receptor Rev‐erbalpha. Gastroenterology 135: 689‐698, 2008.
 70. Dufour CR, Levasseur MP, Pham NH, Eichner LJ, Wilson BJ, Charest‐Marcotte A, Duguay D, Poirier‐Heon JF, Cermakian N, Giguere V. Genomic convergence among ERRalpha, PROX1, and BMAL1 in the control of metabolic clock outputs. PLoS Genet 7: e1002143, 2011.
 71. Duong HA, Robles MS, Knutti D, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science 332: 1436‐1439, 2011.
 72. Durgan DJ, Pat BM, Laczy B, Bradley JA, Tsai JY, Grenett MH, Ratcliffe WF, Brewer RA, Nagendran J, Villegas‐Montoya C, Zou C, Zou L, Johnson RL, Jr, Dyck JR, Bray MS, Gamble KL, Chatham JC, Young ME. O‐GlcNAcylation, novel post‐translational modification linking myocardial metabolism and cardiomyocyte circadian clock. J Biol Chem 286: 44606‐44619, 2011.
 73. Edwards PA, Muroya H, Gould RG. In vivo demonstration of the circadian thythm of cholesterol biosynthesis in the liver and intestine of the rat. J Lipid Res 13: 396‐401, 1972.
 74. Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, Camacho F, Vielhaber EL, Giovanni A, Virshup DM. Control of mammalian circadian rhythm by CKIepsilon‐regulated proteasome‐mediated PER2 degradation. Mol Cell Biol 25: 2795‐2807, 2005.
 75. Eloranta JJ, Kullak‐Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys 433: 397‐412, 2005.
 76. Estall JL, Kahn M, Cooper MP, Fisher FM, Wu MK, Laznik D, Qu L, Cohen DE, Shulman GI, Spiegelman BM. Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha expression. Diabetes 58: 1499‐1508, 2009.
 77. Estep M, Abawi M, Jarrar M, Wang L, Stepanova M, Elariny H, Moazez A, Goodman Z, Chandhoke V, Baranova A, Younossi ZM. Association of obestatin, ghrelin, and inflammatory cytokines in obese patients with non‐alcoholic fatty liver disease. Obes Surg 21: 1750‐1757.
 78. Etchegaray JP, Machida KK, Noton E, Constance CM, Dallmann R, Di Napoli MN, DeBruyne JP, Lambert CM, Yu EA, Reppert SM, Weaver DR. Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol Cell Biol 29: 3853‐3866, 2009.
 79. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med 10: 355‐361, 2004.
 80. Farnell YZ, Allen GC, Nahm SS, Neuendorff N, West JR, Chen WJ, Earnest DJ. Neonatal alcohol exposure differentially alters clock gene oscillations within the suprachiasmatic nucleus, cerebellum, and liver of adult rats. Alcohol Clin Exp Res 32: 544‐552, 2008.
 81. Felber JP, Golay A. Regulation of nutrient metabolism and energy expenditure. Metabolism 44: 4‐9, 1995.
 82. Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, Liu XS, Lazar MA. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331: 1315‐1319, 2011.
 83. Ferre P, Foufelle F. SREBP‐1c transcription factor and lipid homeostasis: Clinical perspective. Horm Res 68: 72‐82, 2007.
 84. Ferre P, Foufelle F. Hepatic steatosis: A role for de novo lipogenesis and the transcription factor SREBP‐1c. Diabetes Obes Metab 12 (Suppl 2): 83‐92, 2010.
 85. Filipski E, Subramanian P, Carriere J, Guettier C, Barbason H, Levi F. Circadian disruption accelerates liver carcinogenesis in mice. Mutat Res 680: 95‐105, 2009.
 86. Finck BN, Kelly DP. PGC‐1 coactivators: Inducible regulators of energy metabolism in health and disease. J Clin Invest 116: 615‐622, 2006.
 87. Franken P, Dudley CA, Estill SJ, Barakat M, Thomason R, O'Hara BF, McKnight SL. NPAS2 as a transcriptional regulator of non‐rapid eye movement sleep: Genotype and sex interactions. Proc Natl Acad Sci U S A 103: 7118‐7123, 2006.
 88. Franken P, Lopez‐Molina L, Marcacci L, Schibler U, Tafti M. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. J Neurosci 20: 617‐625, 2000.
 89. Friedman SL. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88: 125‐172, 2008a.
 90. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 134: 1655‐1669, 2008b.
 91. Froy O, Miskin R. The interrelations among feeding, circadian rhythms and ageing. Prog Neurobiol 82: 142‐150, 2007.
 92. Fu L, Pelicano H, Liu J, Huang P, Lee C. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111: 41‐50, 2002.
 93. Gachon F, Firsov D. The role of circadian timing system on drug metabolism and detoxification. Expert Opin Drug Metab Toxicol 7: 147‐158, 2010.
 94. Gachon F, Leuenberger N, Claudel T, Gos P, Jouffe C, Fleury Olela F, de Mollerat du Jeu X, Wahli W, Schibler U. Proline‐ and acidic amino acid‐rich basic leucine zipper proteins modulate peroxisome proliferator‐activated receptor alpha (PPARalpha) activity. Proc Natl Acad Sci U S A 108: 4794‐4799.
 95. Gachon F, Olela FF, Schaad O, Descombes P, Schibler U. The circadian PAR‐domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab 4: 25‐36, 2006.
 96. Gallego M, Virshup DM. Post‐translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8: 139‐148, 2007.
 97. Garfinkel D, Zisapel N. Liver cirrhosis and circadian rhythm. Ann Intern Med 125: 154, 1996.
 98. Gauldie J, Bonniaud P, Sime P, Ask K, Kolb M. TGF‐beta, Smad3 and the process of progressive fibrosis. Biochem Soc Trans 35: 661‐664, 2007.
 99. Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell 22: 375‐382, 2006.
 100. Gielen J, van Cantfort J, Robaye B, Renson J. Rat‐liver cholesterol 7alpha‐hydroxylase. 3. New results about its circadian rhythm. Eur J Biochem 55: 41‐48, 1975.
 101. Glass JD, Hauser UE, Randolph W, Ferriera S, Rea MA. Suprachiasmatic nucleus neurochemistry in the conscious brain: Correlation with circadian activity rhythms. J Biol Rhythms 8 (Suppl): S47‐S52, 1993.
 102. Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O'Neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM. The after‐hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316: 897‐900, 2007.
 103. Goldfarb S. Regulation of hepatic cholesterogenesis. Int Rev Physiol 21: 317‐356, 1980.
 104. Gonzalez FJ, Shah YM. PPARalpha: Mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology 246: 2‐8, 2008.
 105. Gorbacheva VY, Kondratov RV, Zhang R, Cherukuri S, Gudkov AV, Takahashi JS, Antoch MP. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc Natl Acad Sci U S A 102: 3407‐3412, 2005.
 106. Grechez‐Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F. The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation. J Biol Chem 283: 4535‐4542, 2008.
 107. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell 134: 728‐742, 2008.
 108. Grima B, Lamouroux A, Chelot E, Papin C, Limbourg‐Bouchon B, Rouyer F. The F‐box protein slimb controls the levels of clock proteins period and timeless. Nature 420: 178‐182, 2002.
 109. Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, Amin RH, Granneman JG, Piomelli D, Leff T, Sassone‐Corsi P. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab 12: 509‐520.
 110. Handschin C, Meyer UA. Induction of drug metabolism: The role of nuclear receptors. Pharmacol Rev 55: 649‐673, 2003.
 111. Hansen AP, Johansen K. Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia 6: 27‐33, 1970.
 112. Hardie DG, Carling D, Gamblin SJ. AMP‐activated protein kinase: Also regulated by ADP? Trends Biochem Sci 36: 470‐477, 2011.
 113. Harmer SL, Hogenesch JB, Straume M, Chang HS, Han B, Zhu T, Wang X, Kreps JA, Kay SA. Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290: 2110‐2113, 2000.
 114. Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 5: 189‐200, 2011.
 115. Harris RA, Mapes JP, Ochs RS, Crabb DW, Stropes L. Hormonal control of hepatic lipogenesis. Adv Exp Med Biol 111: 17‐42, 1979.
 116. Harrison SA, Diehl AM. Fat and the liver–a molecular overview. Semin Gastrointest Dis 13: 3‐16, 2002.
 117. Harvey AG. Sleep and circadian functioning: Critical mechanisms in the mood disorders? Annu Rev Clin Psychol 7: 297‐319, 2010.
 118. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Time‐restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high‐fat diet. Cell Metab 15: 848‐860.
 119. Hauw JJ, Hausser‐Hauw C, De Girolami U, Hasboun D, Seilhean D. Neuropathology of sleep disorders: A review. J Neuropathol Exp Neurol 70: 243‐252, 2011.
 120. Hellerstein MK, Schwarz JM, Neese RA. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr 16: 523‐557, 1996.
 121. Hermida RC, Ayala DE, Fernandez JR, Portaluppi F, Fabbian F, Smolensky MH. Circadian rhythms in blood pressure regulation and optimization of hypertension treatment with ACE inhibitor and ARB medications. Am J Hypertens 24: 383‐391, 2010.
 122. Hermida RC, Chayan L, Ayala DE, Mojon A, Fontao MJ, Fernandez JR. Relationship between metabolic syndrome, circadian treatment time, and blood pressure non‐dipping profile in essential hypertension. Chronobiol Int 28: 509‐519, 2011.
 123. Hernandez‐Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 6: 425‐456.
 124. Herzog ED, Takahashi JS, Block GD. Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat Neurosci 1: 708‐713, 1998.
 125. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone‐Corsi P. CLOCK‐mediated acetylation of BMAL1 controls circadian function. Nature 450: 1086‐1090, 2007.
 126. Ho AK, Price DM, Terriff D, and Chik CL. Timing of mitogen‐activated protein kinase (MAPK) activation in the rat pineal gland. Mol Cell Endocrinol 252: 34‐39, 2006.
 127. Hodson L, Frayn KN. Hepatic fatty acid partitioning. Curr Opin Lipidol 22: 216‐224, 2011.
 128. Hofman MA, Swaab DF. Living by the clock: The circadian pacemaker in older people. Ageing Res Rev 5: 33‐51, 2006.
 129. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray‐Grant M, Perdew GH, and Bradfield CA. Characterization of a subset of the basic‐helix‐loop‐helix‐PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 272: 8581‐8593, 1997.
 130. Hosoda H, Kato K, Asano H, Ito M, Kato H, Iwamoto T, Suzuki A, Masushige S, Kida S. CBP/p300 is a cell type‐specific modulator of CLOCK/BMAL1‐mediated transcription. Mol Brain 2: 34, 2009.
 131. Hu X, Lazar MA. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402: 93‐96, 1999.
 132. Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH, Partch C, Green CB, Zhang H, Takahashi JS. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science 337: 189‐194, 2012.
 133. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms, sleep, and metabolism. J Clin Invest 121: 2133‐2141, 2011.
 134. Hughes KA, Webster SP, Walker BR. 11‐Beta‐hydroxysteroid dehydrogenase type 1 (11beta‐HSD1) inhibitors in type 2 diabetes mellitus and obesity. Expert Opin Investig Drugs 17: 481‐496, 2008.
 135. Hurd MW, Ralph MR. The significance of circadian organization for longevity in the golden hamster. J Biol Rhythms 13: 430‐436, 1998.
 136. Ishizuka T, Lazar MA. The N‐CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol Cell Biol 23: 5122‐5131, 2003.
 137. Iwahana E, Akiyama M, Miyakawa K, Uchida A, Kasahara J, Fukunaga K, Hamada T, Shibata S. Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase‐3 protein expression in the mouse suprachiasmatic nuclei. Eur J Neurosci 19: 2281‐2287, 2004.
 138. Iwase T, Kajimura N, Uchiyama M, Ebisawa T, Yoshimura K, Kamei Y, Shibui K, Kim K, Kudo Y, Katoh M, Watanabe T, Nakajima T, Ozeki Y, Sugishita M, Hori T, Ikeda M, Toyoshima R, Inoue Y, Yamada N, Mishima K, Nomura M, Ozaki N, Okawa M, Takahashi K, Yamauchi T. Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Psychiatry Res 109: 121‐128, 2002.
 139. Jeninga EH, Schoonjans K, Auwerx J. Reversible acetylation of PGC‐1: Connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29: 4617‐4624, 2010.
 140. Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284: E671‐678, 2003.
 141. Jimenez‐Ortega V, Cano‐Barquilla P, Scacchi PA, Cardinali DP, Esquifino AI. Cadmium‐induced disruption in 24‐h expression of clock and redox enzyme genes in rat medial basal hypothalamus: Prevention by melatonin. Front Neurol 2: 13, 2011.
 142. Jitrapakdee S. Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. Int J Biochem Cell Biol 44: 33‐45, 2011.
 143. Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptacek LJ. Familial advanced sleep‐phase syndrome: A short‐period circadian rhythm variant in humans. Nat Med 5: 1062‐1065, 1999.
 144. Jones KH, Ellis J, von Schantz M, Skene DJ, Dijk DJ, Archer SN. Age‐related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities. J Sleep Res 16: 12‐16, 2007.
 145. Jones PJ, Schoeller DA. Evidence for diurnal periodicity in human cholesterol synthesis. J Lipid Res 31: 667‐673, 1990.
 146. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 28: 370‐379, 2008.
 147. Jump DB. Fatty acid regulation of hepatic lipid metabolism. Curr Opin Clin Nutr Metab Care 14: 115‐120, 2010.
 148. Kaasik K, Lee CC. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature 430: 467‐471, 2004.
 149. Kafka MS, Marangos PJ, Moore RY. Suprachiasmatic nucleus ablation abolishes circadian rhythms in rat brain neurotransmitter receptors. Brain Res 327: 344‐347, 1985.
 150. Katada S, Sassone‐Corsi P. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17: 1414‐1421, 2010.
 151. Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, Mignot E. A CLOCK polymorphism associated with human diurnal preference. Sleep 21: 569‐576, 1998.
 152. Keesler GA, Camacho F, Guo Y, Virshup D, Mondadori C, Yao Z. Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon. Neuroreport 11: 951‐955, 2000.
 153. Kelly TJ, Lerin C, Haas W, Gygi SP, Puigserver P. GCN5‐mediated transcriptional control of the metabolic coactivator PGC‐1beta through lysine acetylation. J Biol Chem 284: 19945‐19952, 2009.
 154. Keppler D. Multidrug resistance proteins (MRPs, ABCCs): Importance for pathophysiology and drug therapy. Handb Exp Pharmacol 201: 299‐323, 2010.
 155. Khapre RV, Samsa WE, Kondratov RV. Circadian regulation of cell cycle: Molecular connections between aging and the circadian clock. Ann Med 42: 404‐415, 2010.
 156. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802: 396‐405, 2010.
 157. King LA, Toledo AH, Rivera‐Chavez FA, Toledo‐Pereyra LH. Role of p38 and JNK in liver ischemia and reperfusion. J Hepatobiliary Pancreat Surg 16: 763‐770, 2009.
 158. Kirsz K, Zieba DA. Ghrelin‐mediated appetite regulation in the central nervous system. Peptides 32: 2256‐2264.
 159. Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 93: 8455‐8459, 1996.
 160. Ko HW, Jiang J, Edery I. Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature 420: 673‐678, 2002.
 161. Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non‐alcoholic steatohepatitis. Clin Chim Acta 412: 1297‐1305, 2011.
 162. Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C, Kobayashi Y, Turek FW, Bass J. High‐fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 6: 414‐421, 2007.
 163. Kolla BP, Auger RR. Jet lag and shift work sleep disorders: How to help reset the internal clock. Cleve Clin J Med 78: 675‐684, 2011.
 164. Kondratova AA, Dubrovsky YV, Antoch MP, Kondratov RV. Circadian clock proteins control adaptation to novel environment and memory formation. Aging (Albany NY) 2: 285‐297, 2010.
 165. Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U. System‐driven and oscillator‐dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol 5: e34, 2007.
 166. Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ. 11beta‐hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid‐inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A 94: 14924‐14929, 1997.
 167. Koyanagi S, Hamdan AM, Horiguchi M, Kusunose N, Okamoto A, Matsunaga N, Ohdo S. cAMP‐response element (CRE)‐mediated transcription by activating transcription factor‐4 (ATF4) is essential for circadian expression of the Period2 gene. J Biol Chem 286: 32416‐32423, 2011.
 168. Kramer A, Yang FC, Snodgrass P, Li X, Scammell TE, Davis FC, Weitz CJ. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294: 2511‐2515, 2001.
 169. Kraves S, Weitz CJ. A role for cardiotrophin‐like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 9: 212‐219, 2006.
 170. Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR. Circadian polymorphisms associated with affective disorders. J Circadian Rhythms 7: 2, 2009.
 171. Kudo T, Kawashima M, Tamagawa T, Shibata S. Clock mutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet. Am J Physiol Endocrinol Metab 294: E120‐E130, 2008.
 172. Kudo T, Tamagawa T, Kawashima M, Mito N, Shibata S. Attenuating effect of clock mutation on triglyceride contents in the ICR mouse liver under a high‐fat diet. J Biol Rhythms 22: 312‐323, 2007.
 173. Kudo T, Tamagawa T, Shibata S. Effect of chronic ethanol exposure on the liver of Clock‐mutant mice. J Circadian Rhythms 7: 4, 2009.
 174. Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y. DYRK1A and glycogen synthase kinase 3beta, a dual‐kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30: 1757‐1768, 2010.
 175. Kuriyama K, Sasahara K, Kudo T, Shibata S. Daily injection of insulin attenuated impairment of liver circadian clock oscillation in the streptozotocin‐treated diabetic mouse. FEBS Lett 572: 206‐210, 2004.
 176. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: A 10‐year update. Physiol Rev 92: 689‐737, 2012.
 177. Lack LC, Wright HR. Chronobiology of sleep in humans. Cell Mol Life Sci 64: 1205‐1215, 2007.
 178. Lamb TM, Goldsmith CS, Bennett L, Finch KE, Bell‐Pedersen D. Direct transcriptional control of a p38 MAPK pathway by the circadian clock in Neurospora crassa. PLoS One 6: e27149, 2011.
 179. Lamia KA, Papp SJ, Yu RT, Barish GD, Uhlenhaut NH, Jonker JW, Downes M, Evans RM. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480: 552‐556, 2011.
 180. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437‐440, 2009.
 181. Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A 105: 15172‐15177, 2008.
 182. Laposky A, Easton A, Dugovic C, Walisser J, Bradfield C, Turek F. Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. Sleep 28: 395‐409, 2005.
 183. Laposky AD, Bass J, Kohsaka A, Turek FW. Sleep and circadian rhythms: Key components in the regulation of energy metabolism. FEBS Lett 582: 142‐151, 2008.
 184. Laposky AD, Bradley MA, Williams DL, Bass J, Turek FW. Sleep‐wake regulation is altered in leptin‐resistant (db/db) genetically obese and diabetic mice. Am J Physiol Regul Integr Comp Physiol 295: R2059‐2066, 2008.
 185. Lavery DJ, Lopez‐Molina L, Margueron R, Fleury‐Olela F, Conquet F, Schibler U, Bonfils C. Circadian expression of the steroid 15 alpha‐hydroxylase (Cyp2a4) and coumarin 7‐hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Mol Cell Biol 19: 6488‐6499, 1999.
 186. Lavery DJ, Schibler U. Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver‐enriched bZIP protein DBP. Genes Dev 7: 1871‐1884, 1993.
 187. Lavoie JM, Gauthier MS. Regulation of fat metabolism in the liver: Link to non‐alcoholic hepatic steatosis and impact of physical exercise. Cell Mol Life Sci 63: 1393‐1409, 2006.
 188. Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Sasso GL, Moschetta A, Schibler U. REV‐ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol 7: e1000181, 2009.
 189. Leavens KF, Birnbaum MJ. Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol 46: 200‐215, 2011.
 190. Lee H, Chen R, Lee Y, Yoo S, Lee C. Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock. Proc Natl Acad Sci U S A 106: 21359‐21364, 2009.
 191. Lee J, Lee Y, Lee MJ, Park E, Kang SH, Chung CH, Lee KH, Kim K. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol 28: 6056‐6065, 2008.
 192. Lee S, Donehower LA, Herron AJ, Moore DD, Fu L. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One 5: e10995, 2010.
 193. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez‐Salguero PM, Westphal H, Gonzalez FJ. Targeted disruption of the alpha isoform of the peroxisome proliferator‐activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012‐3022, 1995.
 194. Lee Y, Lee J, Kwon I, Nakajima Y, Ohmiya Y, Son GH, Lee KH, Kim K. Coactivation of the CLOCK‐BMAL1 complex by CBP mediates resetting of the circadian clock. J Cell Sci 123: 3547‐3557, 2010.
 195. Lee YH, Alberta JA, Gonzalez FJ, Waxman DJ. Multiple, functional DBP sites on the promoter of the cholesterol 7 alpha‐hydroxylase P450 gene, CYP7. Proposed role in diurnal regulation of liver gene expression. J Biol Chem 269: 14681‐14689, 1994.
 196. Lemberger T, Saladin R, Vazquez M, Assimacopoulos F, Staels B, Desvergne B, Wahli W, Auwerx J. Expression of the peroxisome proliferator‐activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem 271: 1764‐1769, 1996.
 197. Lemmer B. Chronopharmacokinetics: Implications for drug treatment. J Pharm Pharmacol 51: 887‐890, 1999.
 198. Lemmer B. Chronopharmacology and its impact on antihypertensive treatment. Acta Physiol Pharmacol Bulg 24: 71‐80, 1999.
 199. LeSauter J, Hoque N, Weintraub M, Pfaff DW, Silver R. Stomach ghrelin‐secreting cells as food‐entrainable circadian clocks. Proc Natl Acad Sci U S A 106: 13582‐13587, 2009.
 200. Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50: 377‐421, 2010.
 201. Li J, Lu WQ, Beesley S, Loudon AS, Meng QJ. Lithium impacts on the amplitude and period of the molecular circadian clockwork. PLoS One 7: e33292, 2012.
 202. Li S, Liu C, Li N, Hao T, Han T, Hill DE, Vidal M, Lin JD. Genome‐wide coactivation analysis of PGC‐1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab 8: 105‐117, 2008.
 203. Li XM, Delaunay F, Dulong S, Claustrat B, Zampera S, Fujii Y, Teboul M, Beau J, Levi F. Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing. Cancer Res 70: 3351‐3360, 2010.
 204. Li Y, Hai J, Li L, Chen X, Peng H, Cao M, Zhang Q. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non‐alcoholic fatty liver disease development. Endocrine.
 205. Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 14: 9‐19.
 206. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC‐1 family of transcription coactivators. Cell Metab 1: 361‐370, 2005.
 207. Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard CB, Spiegelman BM. Hyperlipidemic effects of dietary saturated fats mediated through PGC‐1beta coactivation of SREBP. Cell 120: 261‐273, 2005.
 208. Lin KK, Kumar V, Geyfman M, Chudova D, Ihler AT, Smyth P, Paus R, Takahashi JS, Andersen B. Circadian clock genes contribute to the regulation of hair follicle cycling. PLoS Genet 5: e1000573, 2009.
 209. Lira VA, Brown DL, Lira AK, Kavazis AN, Soltow QA, Zeanah EH, Criswell DS. Nitric oxide and AMPK cooperatively regulate PGC‐1 in skeletal muscle cells. J Physiol 588: 3551‐3566, 2010.
 210. Liu AC, Welsh DK, Ko CH, Tran HG, Zhang EE, Priest AA, Buhr ED, Singer O, Meeker K, Verma IM, Doyle FJ, 3rd, Takahashi JS, Kay SA. Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129: 605‐616, 2007.
 211. Liu C, Li S, Liu T, Borjigin J, Lin JD. Transcriptional coactivator PGC‐1alpha integrates the mammalian clock and energy metabolism. Nature 447: 477‐481, 2007.
 212. Liu C, Weaver DR, Strogatz SH, Reppert SM. Cellular construction of a circadian clock: Period determination in the suprachiasmatic nuclei. Cell 91: 855‐860, 1997.
 213. Lustig Y, Ruas JL, Estall JL, Lo JC, Devarakonda S, Laznik D, Choi JH, Ono H, Olsen JV, Spiegelman BM. Separation of the gluconeogenic and mitochondrial functions of PGC‐1{alpha} through S6 kinase. Genes Dev 25: 1232‐1244, 2011.
 214. Ma K, Xiao R, Tseng HT, Shan L, Fu L, Moore DD. Circadian dysregulation disrupts bile acid homeostasis. PLoS One 4: e6843, 2009.
 215. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi JS, Bass J. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466: 627‐631.
 216. Maron BJ, Kogan J, Proschan MA, Hecht GM, Roberts WC. Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 23: 1405‐1409, 1994.
 217. Martins IJ, Redgrave TG. Obesity and post‐prandial lipid metabolism. Feast or famine? J Nutr Biochem 15: 130‐141, 2004.
 218. Masoro EJ. Lipids and lipid metabolism. Annu Rev Physiol 39: 301‐321, 1977.
 219. Matsumoto E, Ishihara A, Tamai S, Nemoto A, Iwase K, Hiwasa T, Shibata S, Takiguchi M. Time of day and nutrients in feeding govern daily expression rhythms of the gene for sterol regulatory element‐binding protein (SREBP)‐1 in the mouse liver. J Biol Chem 285: 33028‐33036, 2010.
 220. Matsunaga N, Ikeda M, Takiguchi T, Koyanagi S, Ohdo S. The molecular mechanism regulating 24‐hour rhythm of CYP2E1 expression in the mouse liver. Hepatology 48: 240‐251, 2008.
 221. Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255‐259, 2003.
 222. Maywood ES, O'Neill JS, Chesham JE, Hastings MH. Minireview: The circadian clockwork of the suprachiasmatic nuclei–analysis of a cellular oscillator that drives endocrine rhythms. Endocrinology 148: 5624‐5634, 2007.
 223. Maywood ES, O'Neill JS, Reddy AB, Chesham JE, Prosser HM, Kyriacou CP, Godinho SI, Nolan PM, Hastings MH. Genetic and molecular analysis of the central and peripheral circadian clockwork of mice. Cold Spring Harb Symp Quant Biol 72: 85‐94, 2007.
 224. Maywood ES, Reddy AB, Wong GK, O'Neill JS, O'Brien JA, McMahon DG, Harmar AJ, Okamura H, Hastings MH. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16: 599‐605, 2006.
 225. Mazzoccoli G, Panza A, Valvano MR, Palumbo O, Carella M, Pazienza V, Biscaglia G, Tavano F, Di Sebastiano P, Andriulli A, Piepoli A. Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients. Chronobiol Int 28: 841‐851, 2011.
 226. McCarthy MJ, Nievergelt CM, Shekhtman T, Kripke DF, Welsh DK, Kelsoe JR. Functional genetic variation in the Rev‐Erbalpha pathway and lithium response in the treatment of bipolar disorder. Genes Brain Behav 10: 852‐861, 2011.
 227. Min L, He B, Hui L. Mitogen‐activated protein kinases in hepatocellular carcinoma development. Semin Cancer Biol 21: 10‐20, 2010.
 228. Mishima K, Tozawa T, Satoh K, Saitoh H, Mishima Y. The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet 133B: 101‐104, 2005.
 229. Mitropoulos KA, Balasubramaniam S. The role of glucocorticoids in the regulation of the diurnal rhythm of hepatic beta‐hydroxy‐beta‐methylglutaryl‐coenzyme A reductase and cholesterol 7 alpha‐hydroxylase. Biochem J 160: 49‐55, 1976.
 230. Miyazaki K, Nagase T, Mesaki M, Narukawa J, Ohara O, Ishida N. Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. Biochem J 380: 95‐103, 2004.
 231. Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY. Sleep and circadian abnormalities in patients with cirrhosis: Features of delayed sleep phase syndrome? Metab Brain Dis 24: 427‐439, 2009.
 232. Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocrinology. Mol Cell Endocrinol 349: 91‐104, 2011.
 233. Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 58: 561‐568, 2009.
 234. Nagoshi E, Brown SA, Dibner C, Kornmann B, Schibler U. Circadian gene expression in cultured cells. Methods Enzymol 393: 543‐557, 2005.
 235. Nakagawa H, Okumura N. Coordinated regulation of circadian rhythms and homeostasis by the suprachiasmatic nucleus. Proc Jpn Acad Ser B Phys Biol Sci 86: 391‐409, 2010.
 236. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone‐Corsi P. The NAD+‐dependent deacetylase SIRT1 modulates CLOCK‐mediated chromatin remodeling and circadian control. Cell 134: 329‐340, 2008.
 237. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone‐Corsi P. Circadian control of the NAD +salvage pathway by CLOCK‐SIRT1. Science 324: 654‐657, 2009.
 238. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, Turek FW. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 20: 8138‐8143, 2000.
 239. Noshiro M, Usui E, Kawamoto T, Kubo H, Fujimoto K, Furukawa M, Honma S, Makishima M, Honma K, Kato Y. Multiple mechanisms regulate circadian expression of the gene for cholesterol 7alpha‐hydroxylase (Cyp7a), a key enzyme in hepatic bile acid biosynthesis. J Biol Rhythms 22: 299‐311, 2007.
 240. O'Neill JS, Reddy AB. The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping. Biochem Soc Trans 40: 44‐50, 2012.
 241. Obrietan K, Impey S, Smith D, Athos J, Storm DR. Circadian regulation of cAMP response element‐mediated gene expression in the suprachiasmatic nuclei. J Biol Chem 274: 17748‐17756, 1999.
 242. Ohsaki K, Oishi K, Kozono Y, Nakayama K, Nakayama KI, Ishida N. The role of {beta}‐TrCP1 and {beta}‐TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2. J Biochem 144: 609‐618, 2008.
 243. Oishi K. Disrupted light‐dark cycle induces obesity with hyperglycemia in genetically intact animals. Neuro Endocrinol Lett 30: 458‐461, 2009.
 244. Oishi K, Ohkura N, Kasamatsu M, Fukushima N, Shirai H, Matsuda J, Horie S, Ishida N. Tissue‐specific augmentation of circadian PAI‐1 expression in mice with streptozotocin‐induced diabetes. Thromb Res 114: 129‐135, 2004.
 245. Oishi K, Shirai H, Ishida N. CLOCK is involved in the circadian transactivation of peroxisome‐proliferator‐activated receptor alpha (PPARalpha) in mice. Biochem J 386: 575‐581, 2005.
 246. Oiwa A, Kakizawa T, Miyamoto T, Yamashita K, Jiang W, Takeda T, Suzuki S, Hashizume K. Synergistic regulation of the mouse orphan nuclear receptor SHP gene promoter by CLOCK‐BMAL1 and LRH‐1. Biochem Biophys Res Commun 353: 895‐901, 2007.
 247. Okamatsu Y, Matsuda K, Hiramoto I, Tani H, Kimura K, Yada Y, Kakuma T, Higuchi S, Kojima M, Matsuishi T. Ghrelin and leptin modulate immunity and liver function in overweight children. Pediatr Int 51: 9‐13, 2009.
 248. Oshima T, Takenoshita S, Akaike M, Kunisaki C, Fujii S, Nozaki A, Numata K, Shiozawa M, Rino Y, Tanaka K, Masuda M, Imada T. Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep 25: 1439‐1446, 2011.
 249. Owen OE, Reichard GA, Jr, Patel MS, Boden G. Energy metabolism in feasting and fasting. Adv Exp Med Biol 111: 169‐188, 1979.
 250. Palmer RH. Bile acids, liver injury, and liver disease. Arch Intern Med 130: 606‐617, 1972.
 251. Pan X, Hussain MM. Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J Biol Chem 282: 24707‐24719, 2007.
 252. Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab 12: 174‐186, 2010.
 253. Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab 12: 174‐186.
 254. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307‐320, 2002.
 255. Paschos GK, Baggs JE, Hogenesch JB, FitzGerald GA. The role of clock genes in pharmacology. Annu Rev Pharmacol Toxicol 50: 187‐214, 2010.
 256. Perreau‐Lenz S, Spanagel R. The effects of drugs of abuse on clock genes. Drug News Perspect 21: 211‐217, 2008.
 257. Phiel CJ, Klein PS. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 41: 789‐813, 2001.
 258. Piscaglia F, Siringo S, Hermida RC, Legnani C, Valgimigli M, Donati G, Palareti G, Gramantieri L, Gaiani S, Burroughs AK, Bolondi L. Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices. Hepatology 31: 349‐357, 2000.
 259. Pizzio GA, Hainich EC, Ferreyra GA, Coso OA, Golombek DA. Circadian and photic regulation of ERK, JNK and p38 in the hamster SCN. Neuroreport 14: 1417‐1419, 2003.
 260. Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813: 1619‐1633, 2010.
 261. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: Lessons from genetically engineered mice. J Clin Invest 118: 829‐838, 2008a.
 262. Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab 34: 643‐648, 2008b.
 263. Preitner N, Damiola F, Lopez‐Molina L, Zakany J, Duboule D, Albrecht U, Schibler U. The orphan nuclear receptor REV‐ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251‐260, 2002.
 264. Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator‐1. Mol Cell 8: 971‐982, 2001.
 265. Puigserver P, Spiegelman BM. Peroxisome proliferator‐activated receptor‐gamma coactivator 1 alpha (PGC‐1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24: 78‐90, 2003.
 266. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARalpha: Energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 8: e002, 2010.
 267. Quintero JE, Kuhlman SJ, McMahon DG. The biological clock nucleus: A multiphasic oscillator network regulated by light. J Neurosci 23: 8070‐8076, 2003.
 268. Ralph MR, Lehman MN. Transplantation: A new tool in the analysis of the mammalian hypothalamic circadian pacemaker. Trends Neurosci 14: 362‐366, 1991.
 269. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT‐mediated NAD+ biosynthesis. Science 324: 651‐654, 2009.
 270. Reddy JK. Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta‐oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol 281: G1333‐1339, 2001.
 271. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 290: G852‐858, 2006.
 272. Reid KJ, Chang AM, Dubocovich ML, Turek FW, Takahashi JS, Zee PC. Familial advanced sleep phase syndrome. Arch Neurol 58: 1089‐1094, 2001.
 273. Reid KJ, Zee PC. Circadian rhythm disorders. Semin Neurol 29: 393‐405, 2009.
 274. Reischl S, Kramer A. Kinases and phosphatases in the mammalian circadian clock. FEBS Lett 585: 1393‐1399, 2011.
 275. Reischl S, Vanselow K, Westermark PO, Thierfelder N, Maier B, Herzel H, Kramer A. Beta‐TrCP1‐mediated degradation of PERIOD2 is essential for circadian dynamics. J Biol Rhythms 22: 375‐386, 2007.
 276. Reppert SM, Weaver DR. Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63: 647‐676, 2001.
 277. Rey G, Cesbron F, Rougemont J, Reinke H, Brunner M, Naef F. Genome‐wide and phase‐specific DNA‐binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol 9: e1000595, 2011.
 278. Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM. Regulation of hepatic fasting response by PPARgamma coactivator‐1alpha (PGC‐1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci U S A 100: 4012‐4017, 2003.
 279. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC‐1alpha and SIRT1. Nature 434: 113‐118, 2005.
 280. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2: e377, 2004.
 281. Rudney H, Sexton RC. Regulation of cholesterol biosynthesis. Annu Rev Nutr 6: 245‐272, 1986.
 282. Rusak B, Groos G. Suprachiasmatic stimulation phase shifts rodent circadian rhythms. Science 215: 1407‐1409, 1982.
 283. Rutter J, Reick M, Wu LC, McKnight SL. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293: 510‐514, 2001.
 284. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Jr, Vitiello MV, Zhdanova IV. Circadian rhythm sleep disorders: Part I, basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep 30: 1460‐1483, 2007.
 285. Sack RL, Auckley D, Auger RR, Carskadon MA, Wright KP, Jr, Vitiello MV, Zhdanova IV. Circadian rhythm sleep disorders: Part II, advanced sleep phase disorder, delayed sleep phase disorder, free‐running disorder, and irregular sleep‐wake rhythm. An American Academy of Sleep Medicine review. Sleep 30: 1484‐1501, 2007.
 286. Sahar S, Nin V, Barbosa MT, Chini EN, Sassone‐Corsi P. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation. Aging (Albany NY) 3: 794‐802.
 287. Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone‐Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta‐mediated phosphorylation. PLoS One 5: e8561.
 288. Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone‐Corsi P. Regulation of BMAL1 protein stability and circadian function by GSK3beta‐mediated phosphorylation. PLoS One 5: e8561, 2010.
 289. Sale MV, Ridding MC, Nordstrom MA. Circadian modulation of neuroplasticity in humans and potential therapeutic implications. Rev Neurosci 21: 55‐66, 2010.
 290. Sands WA, Palmer TM. Regulating gene transcription in response to cyclic AMP elevation. Cell Signal 20: 460‐466, 2008.
 291. Sani M, Gadacha W, Boughattas NA, Reinberg A, Ben Attia M. Circadian and ultradian (12 h) rhythms of hepatic thiosulfate sulfurtransferase (rhodanese) activity in mice during the first two months of life. Chronobiol Int 23: 551‐563, 2006.
 292. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43: 527‐537, 2004.
 293. Sato TK, Yamada RG, Ukai H, Baggs JE, Miraglia LJ, Kobayashi TJ, Welsh DK, Kay SA, Ueda HR, Hogenesch JB. Feedback repression is required for mammalian circadian clock function. Nat Genet 38: 312‐319, 2006.
 294. Scarbrough K, Losee‐Olson S, Wallen EP, Turek FW. Aging and photoperiod affect entrainment and quantitative aspects of locomotor behavior in Syrian hamsters. Am J Physiol 272: R1219‐R1225, 1997.
 295. Schibler U. The 2008 Pittendrigh/Aschoff lecture: Peripheral phase coordination in the mammalian circadian timing system. J Biol Rhythms 24: 3‐15, 2009.
 296. Schlierf G, Dorow E. Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate‐induction in man and their modification by nocturnal suppression of lipolysis. J Clin Invest 52: 732‐740, 1973.
 297. Schmutz I, Ripperger JA, Baeriswyl‐Aebischer S, Albrecht U. The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev 24: 345‐357, 2010.
 298. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator‐activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 37: 907‐925, 1996.
 299. Schultze AE, Alborn WE, Newton RK, Konrad RJ. Administration of a PPARalpha agonist increases serum apolipoprotein A‐V levels and the apolipoprotein A‐V/apolipoprotein C‐III ratio. J Lipid Res 46: 1591‐1595, 2005.
 300. Schwartz WJ, Gainer H. Suprachiasmatic nucleus: Use of 14C‐labeled deoxyglucose uptake as a functional marker. Science 197: 1089‐1091, 1977.
 301. Scott EM, Carter AM, Grant PJ. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (Lond) 32: 658‐662, 2008.
 302. Scott EM, Carter AM, Grant PJ. Diabetes and cardiovascular disease: Related disorders created by disturbances in the endogenous clock. J Indian Med Assoc 106: 736‐738, 740, 2008.
 303. Seaman GV, Engel R, Swank RL, Hissen W. Circadian periodicity in some physicochemical parameters of circulating blood. Nature 207: 833‐835, 1965.
 304. Sensi S. Some aspects of circadian variations of carbohydrate metabolism and related hormones in man. Chronobiologia 1: 396‐404, 1974.
 305. Servillo G, Della Fazia MA, Sassone‐Corsi P. Coupling cAMP signaling to transcription in the liver: Pivotal role of CREB and CREM. Exp Cell Res 275: 143‐154, 2002.
 306. Seth D, Haber PS, Syn WK, Diehl AM, Day CP. Pathogenesis of alcohol‐induced liver disease: Classical concepts and recent advances. J Gastroenterol Hepatol 26: 1089‐1105, 2012.
 307. Shaywitz AJ, Greenberg ME. CREB: A stimulus‐induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68: 821‐861, 1999.
 308. Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Jr, and Reppert SM. Two period homologs: Circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19: 1261‐1269, 1997.
 309. Sherman H, Frumin I, Gutman R, Chapnik N, Lorentz A, Meylan J, le Coutre J, Froy O. Long‐term restricted feeding alters circadian expression and reduces the level of inflammatory and disease markers. J Cell Mol Med 15: 2745‐2759.
 310. Shibata S, Tahara Y, Hirao A. The adjustment and manipulation of biological rhythms by light, nutrition, and abused drugs. Adv Drug Deliv Rev 62: 918‐927.
 311. Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, Tezuka M, Kosuge Y, Ishige K, Ito Y, Komiyama K, Okamatsu‐Ogura Y, Kimura K, Saito M. Deficient of a clock gene, brain and muscle Arnt‐like protein‐1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One 6: e25231, 2011.
 312. Shirogane T, Jin J, Ang XL, Harper JW. SCFbeta‐TRCP controls clock‐dependent transcription via casein kinase 1‐dependent degradation of the mammalian period‐1 (Per1) protein. J Biol Chem 280: 26863‐26872, 2005.
 313. Siepka SM, Yoo SH, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS. Circadian mutant Overtime reveals F‐box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129: 1011‐1023, 2007.
 314. Silver R, Schwartz WJ. The suprachiasmatic nucleus is a functionally heterogeneous timekeeping organ. Methods Enzymol 393: 451‐465, 2005.
 315. Slot AJ, Molinski SV, Cole SP. Mammalian multidrug‐resistance proteins (MRPs). Essays Biochem 50: 179‐207, 2011.
 316. So AY, Bernal TU, Pillsbury ML, Yamamoto KR, Feldman BJ. Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proc Natl Acad Sci U S A 106: 17582‐17587, 2009.
 317. Sookoian S, Castano G, Gemma C, Gianotti TF, Pirola CJ. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J Gastroenterol 13: 4242‐4248, 2007.
 318. Srinivasan V, Singh J, Pandi‐Perumal SR, Brown GM, Spence DW, Cardinali DP. Jet lag, circadian rhythm sleep disturbances, and depression: The role of melatonin and its analogs. Adv Ther 27: 796‐813, 2010.
 319. Staels B. When the Clock stops ticking, metabolic syndrome explodes. Nat Med 12: 54‐55; discussion 55, 2006.
 320. Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH. Chronic inflammation, immune escape and oncogenesis in the liver: A unique neighborhood for novel intersections. Hepatology 56 (4): 1567‐1574, 2012.
 321. Steindl PE, Finn B, Bendok B, Rothke S, Zee PC, Blei AT. Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med 123: 274‐277, 1995.
 322. Storch KF, Weitz CJ. Daily rhythms of food‐anticipatory behavioral activity do not require the known circadian clock. Proc Natl Acad Sci U S A 106: 6808‐6813, 2009.
 323. Su W, Guo Z, Randall DC, Cassis L, Brown DR, Gong MC. Hypertension and disrupted blood pressure circadian rhythm in type 2 diabetic db/db mice. Am J Physiol Heart Circ Physiol 295: H1634‐1641, 2008.
 324. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nat Rev Genet 9: 764‐775, 2008.
 325. Takahata S, Ozaki T, Mimura J, Kikuchi Y, Sogawa K, Fujii‐Kuriyama Y. Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3. Genes Cells 5: 739‐747, 2000.
 326. Takano A, Uchiyama M, Kajimura N, Mishima K, Inoue Y, Kamei Y, Kitajima T, Shibui K, Katoh M, Watanabe T, Hashimotodani Y, Nakajima T, Ozeki Y, Hori T, Yamada N, Toyoshima R, Ozaki N, Okawa M, Nagai K, Takahashi K, Isojima Y, Yamauchi T, Ebisawa T. A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology 29: 1901‐1909, 2004.
 327. Tessari P, Coracina A, Cosma A, Tiengo A. Hepatic lipid metabolism and non‐alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 19: 291‐302, 2009.
 328. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander‐Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high‐fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295: G987‐995, 2008.
 329. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291: 1040‐1043, 2001.
 330. Towle HC, Kaytor EN, Shih HM. Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu Rev Nutr 17: 405‐433, 1997.
 331. Trak‐Smayra V, Paradis V, Massart J, Nasser S, Jebara V, Fromenty B. Pathology of the liver in obese and diabetic ob/ob and db/db mice fed a standard or high‐calorie diet. Int J Exp Pathol 92: 413‐421, 2011.
 332. Trausch‐Azar J, Leone TC, Kelly DP, Schwartz AL. Ubiquitin proteasome‐dependent degradation of the transcriptional coactivator PGC‐1{alpha} via the N‐terminal pathway. J Biol Chem 285: 40192‐40200, 2010.
 333. Travnickova‐Bendova Z, Cermakian N, Reppert SM, Sassone‐Corsi P. Bimodal regulation of mPeriod promoters by CREB‐dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci U S A 99: 7728‐7733, 2002.
 334. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee‐Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308: 1043‐1045, 2005.
 335. Um JH, Pendergast JS, Springer DA, Foretz M, Viollet B, Brown A, Kim MK, Yamazaki S, Chung JH. AMPK regulates circadian rhythms in a tissue‐ and isoform‐specific manner. PLoS One 6: e18450, 2011.
 336. Um JH, Pendergast JS, Springer DA, Foretz M, Viollet B, Brown A, Kim MK, Yamazaki S, Chung JH. AMPK regulates circadian rhythms in a tissue‐ and isoform‐specific manner. PLoS One 6: e18450, 2011.
 337. Um JH, Yang S, Yamazaki S, Kang H, Viollet B, Foretz M, Chung JH. Activation of 5’‐AMP‐activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)‐dependent degradation of clock protein mPer2. J Biol Chem 282: 20794‐20798, 2007.
 338. Uribe M, Zamora‐Valdes D, Moreno‐Portillo M, Bermejo‐Martinez L, Pichardo‐Bahena R, Baptista‐Gonzalez HA, Ponciano‐Rodriguez G, Uribe MH, Medina‐Santillan R, Mendez‐Sanchez N. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol 7: 67‐71, 2008.
 339. van den Heiligenberg S, Depres‐Brummer P, Barbason H, Claustrat B, Reynes M, Levi F. The tumor promoting effect of constant light exposure on diethylnitrosamine‐induced hepatocarcinogenesis in rats. Life Sci 64: 2523‐2534, 1999.
 340. van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D, Hoeijmakers JH, Yasui A. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627‐630, 1999.
 341. van Esseveldt KE, Lehman MN, Boer GJ. The suprachiasmatic nucleus and the circadian time‐keeping system revisited. Brain Res Brain Res Rev 33: 34‐77, 2000.
 342. van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid‐mediated diabetogenic effects: Towards expansion of therapeutic options? Eur J Clin Invest 39: 81‐93, 2009.
 343. Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, Korte T, Herrmann A, Herzel H, Schlosser A, Kramer A. Differential effects of PER2 phosphorylation: Molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 20: 2660‐2672, 2006.
 344. Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, Lantier L, Hebrard S, Devin‐Leclerc J, Beauloye C, Foretz M, Andreelli F, Ventura‐Clapier R, Bertrand L. AMPK: Lessons from transgenic and knockout animals. Front Biosci 14: 19‐44, 2009.
 345. Viollet B, Lantier L, Devin‐Leclerc J, Hebrard S, Amouyal C, Mounier R, Foretz M, Andreelli F. Targeting the AMPK pathway for the treatment of Type 2 diabetes. Front Biosci 14: 3380‐3400, 2009.
 346. Virshup DM, Eide EJ, Forger DB, Gallego M, Harnish EV. Reversible protein phosphorylation regulates circadian rhythms. Cold Spring Harb Symp Quant Biol 72: 413‐420, 2007.
 347. Viswanathan N, Davis FC. Suprachiasmatic nucleus grafts restore circadian function in aged hamsters. Brain Res 686: 10‐16, 1995.
 348. Vitalini MW, de Paula RM, Goldsmith CS, Jones CA, Borkovich KA, Bell‐Pedersen D. Circadian rhythmicity mediated by temporal regulation of the activity of p38 MAPK. Proc Natl Acad Sci U S A 104: 18223‐18228, 2007.
 349. Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264: 719‐725, 1994.
 350. Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, Fruechte EM, Hitomi K, Thresher RJ, Ishikawa T, Miyazaki J, Takahashi JS, Sancar A. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc Natl Acad Sci U S A 96: 12114‐12119, 1999.
 351. Vollmers C, Gill S, DiTacchio L, Pulivarthy SR, Le HD, Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc Natl Acad Sci U S A 106: 21453‐21458, 2009.
 352. Vosko AM, Schroeder A, Loh DH, Colwell CS. Vasoactive intestinal peptide and the mammalian circadian system. Gen Comp Endocrinol 152: 165‐175, 2007.
 353. Wang HJ, Gao B, Zakhari S, Nagy LE. Inflammation in alcoholic liver disease. Annu Rev Nutr 32: 343‐368, 2012.
 354. Waxman DJ. P450 gene induction by structurally diverse xenochemicals: Central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369: 11‐23, 1999.
 355. Welsh DK, Logothetis DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14: 697‐706, 1995.
 356. Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: Cell autonomy and network properties. Annu Rev Physiol 72: 551‐577, 2010.
 357. Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol 14: 2289‐2295, 2004.
 358. Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab 13: 444‐451, 2002.
 359. Wijayanti N, Katz N, Immenschuh S. Biology of heme in health and disease. Curr Med Chem 11: 981‐986, 2004.
 360. Wijnen H, Young MW. Interplay of circadian clocks and metabolic rhythms. Annu Rev Genet 40: 409‐448, 2006.
 361. Wisor JP, O'Hara BF, Terao A, Selby CP, Kilduff TS, Sancar A, Edgar DM, Franken P. A role for cryptochromes in sleep regulation. BMC Neurosci 3: 20, 2002.
 362. Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, Farrall M, Gauguier D. Aryl hydrocarbon receptor nuclear translocator‐like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A 104: 14412‐14417, 2007.
 363. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA. Negative feedback maintenance of heme homeostasis by its receptor, Rev‐erbalpha. Genes Dev 23: 2201‐2209, 2009.
 364. Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci 11: 589‐599, 2010.
 365. Wyatt JK. Delayed sleep phase syndrome: Pathophysiology and treatment options. Sleep 27: 1195‐1203, 2004.
 366. Xie W, Yeuh MF, Radominska‐Pandya A, Saini SP, Negishi Y, Bottroff BS, Cabrera GY, Tukey RH, Evans RM. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci U S A 100: 4150‐4155, 2003.
 367. Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care 29: 657‐661, 2006.
 368. Yagita K, Okamura H. Forskolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat‐1 fibroblasts. FEBS Lett 465: 79‐82, 2000.
 369. Yamaguchi S, Mitsui S, Miyake S, Yan L, Onishi H, Yagita K, Suzuki M, Shibata S, Kobayashi M, Okamura H. The 5’ upstream region of mPer1 gene contains two promoters and is responsible for circadian oscillation. Curr Biol 10: 873‐876, 2000.
 370. Yamajuku D, Okubo S, Haruma T, Inagaki T, Okuda Y, Kojima T, Noutomi K, Hashimoto S, Oda H. Regular feeding plays an important role in cholesterol homeostasis through the liver circadian clock. Circ Res 105: 545‐548, 2009.
 371. Yamajuku D, Shibata Y, Kitazawa M, Katakura T, Urata H, Kojima T, Nakata O, Hashimoto S. Identification of functional clock‐controlled elements involved in differential timing of Per1 and Per2 transcription. Nucleic Acids Res 38: 7964‐7973, 2010.
 372. Yamazaki S, Straume M, Tei H, Sakaki Y, Menaker M, Block GD. Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci U S A 99: 10801‐10806, 2002.
 373. Yang S, Liu A, Weidenhammer A, Cooksey RC, McClain D, Kim MK, Aguilera G, Abel ED, Chung JH. The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology 150: 2153‐2160, 2009.
 374. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear receptor expression links the circadian clock to metabolism. Cell 126: 801‐810, 2006.
 375. Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K. p38 MAP kinase inhibitors as potential therapeutic drugs for neural diseases. Cent Nerv Syst Agents Med Chem 11: 45‐59, 2010.
 376. Yin L, Joshi S, Wu N, Tong X, Lazar MA. E3 ligases Arf‐bp1 and Pam mediate lithium‐stimulated degradation of the circadian heme receptor Rev‐erb alpha. Proc Natl Acad Sci U S A 107: 11614‐11619, 2010.
 377. Yin L, Lazar MA. The orphan nuclear receptor Rev‐erbalpha recruits the N‐CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol Endocrinol 19: 1452‐1459, 2005.
 378. Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev‐erbalpha is a critical lithium‐sensitive component of the circadian clock. Science 311: 1002‐1005, 2006.
 379. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA. Rev‐erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318: 1786‐1789, 2007.
 380. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC‐1. Nature 413: 131‐138, 2001.
 381. Yoshida Y, Iigusa H, Wang N, Hasunuma K. Cross‐talk between the cellular redox state and the circadian system in Neurospora. PLoS One 6: e28227.
 382. You M, Crabb DW. Recent advances in alcoholic liver disease II. Minireview: Molecular mechanisms of alcoholic fatty liver. Am J Physiol Gastrointest Liver Physiol 287: G1‐6, 2004.
 383. You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW. The role of AMP‐activated protein kinase in the action of ethanol in the liver. Gastroenterology 127: 1798‐1808, 2004.
 384. You M, Rogers CQ. Adiponectin: A key adipokine in alcoholic fatty liver. Exp Biol Med (Maywood) 234: 850‐859, 2009.
 385. Zelber‐Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: An overview of the epidemiological evidence. World J Gastroenterol 17: 3377‐3389, 2011.
 386. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16: 1152‐1156, 2010.
 387. Zhang YK, Yeager RL, Klaassen CD. Circadian expression profiles of drug‐processing genes and transcription factors in mouse liver. Drug Metab Dispos 37: 106‐115, 2009.
 388. Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S, Li Q, Sun ZS, Eichele G, Bradley A, Lee CC. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105: 683‐694, 2001.
 389. Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400: 169‐173, 1999.
 390. Zheng X, Yang Z, Yue Z, Alvarez JD, Sehgal A. FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress. Proc Natl Acad Sci U S A 104: 15899‐15904, 2007.
 391. Zmrzljak UP, Rozman D. Circadian regulation of the hepatic endobiotic and xenobitoic detoxification pathways: The time matters. Chem Res Toxicol 25: 811‐824, 2012.

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Xin Tong, Lei Yin. Circadian Rhythms in Liver Physiology and Liver Diseases. Compr Physiol 2013, 3: 917-940. doi: 10.1002/cphy.c120017