Comprehensive Physiology Wiley Online Library
Home Browse Topics Latest Articles All Issues

Regulation of Ketogenesis in Liver

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Roles of Insulin and Glucagon in Substrate Supply for Hepatic Ketogenesis
2 Effects of Ketones on the Endocrine Pancreas and Adipose Tissue
3 Intrahepatic Partitioning of Fatty Acids Between Oxidation and Esterification
3.1 Pancreatic Hormone Effects on Enzyme Substrate Availability
3.2 Expression of Enzyme Activity
3.3 Role of Malonyl CoA
3.4 Role of Carnitine Palmitoyltransferase I Membrane Topology and Membrane‐Protein Interactions
3.5 Control of Carnitine Palmitoyltransferase I over Ketogenesis: Effects of Altered Insulin Status
3.6 In Vivo Monitoring of Hepatic Acyl‐CoA Partitioning
4 Intramitochondrial Regulation of Ketogenesis
4.1 Modulation of Mitochondrial 3‐Hydroxy‐3‐Methylglutaryl‐CoA Synthase Activity
4.2 Examples of Physiological Conditions Involving Pancreatic Hormone Regulation of Ketogenesis
5 General Comments
Figure 1. Figure 1.

Pathway leading from entry of long‐chain fatty acids into liver cells to formation of ketone bodies, showing the two major branch points involved in determining the fats of cytosolic acyl CoA and intramitochondrial acetyl CoA. The relationship between fatty acid synthesis and oxidation, mediated through inhibition of carnitine palmitoyltransferase I (CPT I) by malonyl CoA, is also shown. GPAT, glycerol‐3‐phosphate acyltransferase; C‐ACT, carnitine‐acylcarnitine translocase; FA, Fatty Acids; HMG, 3‐hydroxy‐3‐methylglutaryl.

Figure 2. Figure 2.

Complex interactions between the effects of insulin and glucagon mediated through their effects on hepatic malonyl‐CoA levels (through their action on acetyl‐CoA carboxylase, ACC) and on mitochondrial (mito) glycerol‐3‐phosphate acyltransferase (GPAT) and mitochondrial β oxidation, respectively. er, endoplasmic reticulum; CPT‐I carnitine palmitoyltransferase I.

Figure 3. Figure 3.

Effects of elevated insulin/glucagon molar concentrations on metabolism of fatty acids (FA), triacylglycerols (TAG), and ketone bodies in vivo. In insulin‐resistant states, the effects of insulin on all three tissues are blunted, resulting in chronically elevated plasma non‐esterified fatty acids (NEFA) and increased triacylglycerol secretion and mitochondrial β‐oxidation of fatty acids in liver. VLDL, very‐low‐density lipoproteins. Fluxes of substrates between tissues are denoted by solid lines. Regulatory interactions are denoted by broken lines. The effect of insulin on hepatic triacylglycerol secretion is bi‐direction, depending on the physiological state: stimulatory in normoinsulinaemic and inhibitory in hypo‐insulinaemic states [].



Figure 1.

Pathway leading from entry of long‐chain fatty acids into liver cells to formation of ketone bodies, showing the two major branch points involved in determining the fats of cytosolic acyl CoA and intramitochondrial acetyl CoA. The relationship between fatty acid synthesis and oxidation, mediated through inhibition of carnitine palmitoyltransferase I (CPT I) by malonyl CoA, is also shown. GPAT, glycerol‐3‐phosphate acyltransferase; C‐ACT, carnitine‐acylcarnitine translocase; FA, Fatty Acids; HMG, 3‐hydroxy‐3‐methylglutaryl.



Figure 2.

Complex interactions between the effects of insulin and glucagon mediated through their effects on hepatic malonyl‐CoA levels (through their action on acetyl‐CoA carboxylase, ACC) and on mitochondrial (mito) glycerol‐3‐phosphate acyltransferase (GPAT) and mitochondrial β oxidation, respectively. er, endoplasmic reticulum; CPT‐I carnitine palmitoyltransferase I.



Figure 3.

Effects of elevated insulin/glucagon molar concentrations on metabolism of fatty acids (FA), triacylglycerols (TAG), and ketone bodies in vivo. In insulin‐resistant states, the effects of insulin on all three tissues are blunted, resulting in chronically elevated plasma non‐esterified fatty acids (NEFA) and increased triacylglycerol secretion and mitochondrial β‐oxidation of fatty acids in liver. VLDL, very‐low‐density lipoproteins. Fluxes of substrates between tissues are denoted by solid lines. Regulatory interactions are denoted by broken lines. The effect of insulin on hepatic triacylglycerol secretion is bi‐direction, depending on the physiological state: stimulatory in normoinsulinaemic and inhibitory in hypo‐insulinaemic states [].

References
 1. Balasse, E. O., and F. Fery. Ketone body production and disposal: effects of fasting, diabetes and exercise. Diabetes Metab. Rev. 5: 247–270, 1989.
 2. Bartlett, K., P. Bartlett, N. Bartlett, and H. S. A. Sherratt. Kinetics of enzymes requiring long‐chain acyl‐CoA esters as substrates: effects of substrate binding to albumin. Biochem. J. 229: 559–560, 1985.
 3. Bates, E. J., and E. D. Saggerson. A selective decrease in mitochondrial glycerol phosphate acyltransferase activity in livers from streptozotocin‐diabetic rats. FEBS Lett. 84: 229–232, 1977.
 4. Bates, E. J., D. L. Topping, S. P. Sooraana, E. D. Saggerson, and P. A. Mayes. Acute effects of insulin on glycerol phosphate acyltransferase activity, ketogenesis and serum free fatty acid concentration in perfused rat liver. FEBS Lett. 84: 225–228, 1977.
 5. Bhuiyan, J., P. H. Pritchard, S. V. Pande, and D. W. Seccombe. Effects of high‐fat diet and fasting on levels of acyl‐coenzyme A binding protein in liver, kidney and heart of rat. Metab. Clin. Exp. 44: 1185–1189, 1995.
 6. Biden, T., and K. W. Taylor. Effects of ketone bodies on insulin release and islet‐cell metabolism in the rat. Biochem. J. 212: 371–377, 1983.
 7. Björntorp, P.. Effect of ketone bodies on lipolysis in adipose tissue in vitro. J. Lipid Res. 7: 621–626, 1966.
 8. Björntorp, P. and T. Scherstén. Effect of β‐hydroxybutyrate on lipid mobilisation. Am. J. Physiol. 212: 683–687, 1967.
 9. Boon, M. R., and V. A. Zammit. Use of a selectively permeabilized isolated rat hepatocyte preparation to study changes in the properties of overt carnitine palmitoyltransferase activity in situ. Biochem. J. 249: 645–652, 1988.
 10. Borthwick, A. C., N. J. Edgell, and R. M. Denton. Protein‐serine kinase from rat epididymal adipose tissue which phosphorylates and activates acetyl‐CoA carboxylase. Possible role in insulin action. Biochem. J. 270: 795–801, 1990.
 11. Brass, E. P. and C. L. Hoppel. Carnitine metabolism in the fasting rat. J. Biol. Chem. 253: 2688–2693, 1978.
 12. Brindle, N. P. J., V. A. Zammit, and C. I. Pogson. Regulation of carnitine palmitoyltransferase activity by malonyl CoA in mitochondria from sheep liver, a tissue with a low capacity for fatty acid synthesis. Biochem. J. 232: 177–182, 1985.
 13. Brown, N. F., V. Esser, D. W. Foster, and J. D. McGarry. Expression of a cDNA for rat liver carnitine palmitoyltransferase I in yeast establishes that catalytic activity and malonyl‐CoA sensitivity reside in a single polypeptide. J. Biol. Chem. 269: 26438–26442, 1994.
 14. Carlson, M. G., W. L. Snead, and P. J. Campbell. Regulation of free fatty acid metabolism by glucagon. J. Clin. Endocrinol. Metab. 77: 11–15, 1993.
 15. Casals, N., N. Roca, M. Guerrero, A. Gil‐Gomez, J. Ayte, C. J. Ciudad, and F. G. Hegardt. Regulation of the expression of the mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase gene. Its role in the control of ketogenesis. Biochem. J. 283: 261–264, 1992.
 16. Chatelain, F., C. Kohl, V. Esser, J. D. McGarry, J. Girard, and J.‐P. Pegorier. Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured foetal rat hepatocytes. Eur. J. Biochem. 235: 789–798, 1996.
 17. Cook, G. A.. Differences in the sensitivity of carnitine palmitoyltransferase to inhibition by malonyl‐CoA are due to differences in Ki values. J. Biol. Chem. 259: 12030–12033, 1984.
 18. Cook, G. A., M. T. King, and R. L. Veech. Ketogenesis and malonyl‐CoA content of isolated rat hepatocytes. J. Biol. Chem. 253: 2529–2531, 1978.
 19. Cook, G. A., R. C. Nielsen, R. A. Hawkins, M. A. Mehlman, M. R. Lakshmanan, and R. L. Veech. Effect of glucagon on hepatic malonyl‐coenzyme A concentration and on lipid synthesis. J. Biol. Chem. 252: 4421–4424, 1977.
 20. Cook, G. A., D. A. Otto, and N. W. Cornell. Differential inhibition of ketogenesis by malonyl‐CoA in mitochondria from fed and starved rats. Biochem. J. 192: 955–958, 1980.
 21. Dashti, N., and J. A. Ontko. Rate‐limiting function of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A synthase in ketogenesis. Biochem. Med. 22: 365–374, 1979.
 22. Drynan, L., P. A. Quant, and V. A. Zammit. Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over β‐oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states. Biochem. J. 317: 791–795, 1996.
 23. Drynan, L., P. A. Quant, and V. A. Zammit. The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat. Biochem. J. 318: 767–770, 1996.
 24. Easom, R. A., and V. A. Zammit. Effects of diabetes on the expressed and total activities of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase in rat liver in vivo. Biochem. J. 230: 747–752, 1985.
 25. Esser, V., N. F. Brown, A. T. Cowan, D. W. Foster, and J. D. McGarry. Expression of a cDNA isolated from rat brown adipose tissue and heart identifies the product as the muscle isoform of carnitine palmitoyltransferase I (M‐CPT I). J. Biol. Chem. 271: 6972–6977, 1996.
 26. Farrell, S., J. Vogel, and L. L. Bieber. Entry of acetyl‐L‐carnitine into biosynthetic pathways. Biochim. Biophys. Acta 876: 175–177, 1986.
 27. Ferranini, E., E. J. Barrett, S. Bevilacqua, and R. A. De Frozno. Effect of fatty acids on glucose production and utilisation in man. J. Clin. Invest. 72: 1737–1747, 1983.
 28. Foley, J. E.. Rationale and application of fatty acid oxidation inhibitors in the treatment of diabetes mellitus. Diabetes Care 15: 773–784, 1992.
 29. Fraser, F., C. G. Corstorphine, and V. A. Zammit. Evidence that both the acyl‐CoA and malonyl‐CoA binding sites of mitochondrial overt carnitine palmitoyltransferase (CPT I) are exposed on the cytosolic face of the outer membrane. Biochem. Soc. Trans. 24: 184, 1996.
 30. Fraser, F., C. G. Corstorphine, and V. A. Zammit. Topology of carnitine palmitoyltransferase in the mitochondrial outer membrane. Biochem. J. 323: 711–718, 1997.
 31. Fraser, F., and V. A. Zammit. Enrichment of carnitine palmitoyltransferase I and II in the contact sites of rat liver mitochondria. Biochem. J. 329: 225–229, 1998.
 32. Frolov, A., and F. Schroeder. Acyl coenzyme A binding protein. Conformational sensitivity to long chain fatty acyl‐CoA. J. Biol. Chem. 273: 11049–11055, 1998.
 33. Galbo, H.. Hormonal Adaptations to Exercise. New York: Thieme‐Stratton, 1983.
 34. Garland, P. B., D. Shepherd, D. G. Nicholls, and J. Ontko. Energy‐dependent control of the tricarboxylic acid cycle by fatty acid oxidation in rat liver mitochondria. Adv. Enzyme Regul. 6: 3–31, 1968.
 35. Grantham, B. D., and V. A. Zammit. Restoration of the properties of carnitine palmitoyltransferase I in liver mitochondria during refeeding of starved rats. Biochem. J. 239: 485–488, 1986.
 36. Grantham, B. D., and V. A. Zammit. Role of carnitine palmitoyltransferase I in the regulation of hepatic ketogenesis during the onset and reversal of diabetes. Biochem. J. 249: 409–414, 1988.
 37. Groop, L., R. Bonadonna, K. Ratheiser, and K. Zych. Suppression of FFA turnover and FFA oxidation by insulin is impaired in NIDDM. Diabetes 35 (Suppl. 1): 39A, 1986.
 38. Guzman, M., and J. Castro. Ethanol increases the sensitivity of carnitine palmitoyltransferase 1 to inhibition by malonyl‐CoA in short‐term incubations. Biochim. Biophys. Acta 1002: 405–408, 1989.
 39. Guzman, M., M. J. H. Geelen, and R. Harris. Effects of proglycosyn (LY177507) on fatty acid metabolism in rat hepatocytes. Arch. Biochem. Biophys. 305: 141–146, 1993.
 40. Guzman, M., M. P. Kolodziej, A. Caldwell, C. G. Corstorphine, and V. A. Zammit. Evidence against direct involvement of phosphorylation in the activation of carnitine palmitoyltransferase by okadaic acid in rat hepatocytes. Biochem. J. 300: 693–699, 1994.
 41. Hardie, D. G.. Regulation of fatty acid synthesis via phosphorylation of acetyl‐CoA carboxylase. Prog. Lipid Res. 20: 117–146, 1989.
 42. Haystead, T. A. J., and D. G. Hardie. Evidence that activation of acetyl‐CoA carboxylase by insulin in adipocytes is mediated by a low‐Mr effector and not by increased phosphorylation. Biochem. J. 240: 99–106, 1986.
 43. Hellman, D. E., B. Senior, and H. M. Goodman. Anti‐lipolytic effects of β‐hydroxybutyrate. Metabolism 18: 906–915, 1969.
 44. Henry, R. R., G. Brechtel, and K.‐H. Lim. Effects of ketone bodies on carbohydrate metabolism in non‐insulin‐dependent (type II) diabetes mellitus. Metabolism 39: 853–858, 1990.
 45. Hirsh, I. B., J. C. Marker, L. J. Smith, R. Spina, C. A. Parvin, J. D. Cryer, and P. E. Cryer. Insulin and glucagon in the prevention of hypoglycaemia during exercise in humans. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E695–E704, 1991.
 46. Holder, J. C., V. A. Zammit, and D. S. Robinson. The preferential uptake of very‐low‐density lipoprotein cholesteryl ester by rat liver in vivo. Biochem. J. 272: 735–741, 1990.
 47. Honnor, R. C., G. S. Dhillon, and C. Londos. cAMP‐dependent protein kinase and lipolysis in rat adipocytes. II Definition of steady‐state relationship with lipolytic and antilipolytic modulators. J. Biol. Chem. 260: 15130–15138, 1985.
 48. Hoppel, C. L., and S. M. Genuth. Urinary excretion of acetylcarnitine during human diabetic and fasting ketosis. Am. J. Physiol. 243 (Endocrinol. Metab. 6): E168–172, 1982.
 49. Huth, W., E. Dierich, V. Oeynhausen, and W. Seubert. On the mechanism of ketogenesis and its control. I On a possible role of acetoacetyl‐CoA thiolase in the control of ketone body production. Biol. Chem. Hoppe‐Seyler 354: 635–649, 1973.
 50. Huth, W., and R. Menke. Regulation of ketogenesis. Mitochodrial acetyl‐CoA acetyltransferase from rat liver. Eur. J. Biochem. 128: 413–419, 1982.
 51. Ide, T., and J. A. Ontko. Increased secretion of very low density lipoprotein triglyceride following inhibition of long chain fatty acid oxidation in isolated rat liver. J. Biol. Chem. 256: 10247–10255, 1981.
 52. Ikeda, T., T. Yoshida, Y. Ito, I. Murakami, O. Mokuda, M. Tominaga, and H. Mashiba. Effect of β‐hydroxybutyrate and acetoacetate on insulin and glucagon secretion from perfused rat pancreas. Arch. Biochem. Biophys. 257: 140–143, 1987.
 53. Ip, M. I., C. Ip, H. M. Tepperman, and J. Tepperman. Effect of adaptation to meal‐feeding on insulin, glucagon and cyclic nucleotide‐protein kinase system in rats. J. Nutr. 107: 746–757, 1977.
 54. Johnson, R. H., J. L. Walton, H. A. Krebs, and D. H. Williamson. Metabolic fuels during and after severe exercise in athletes and non‐athletes. Lancet 2: 452–55, 1969.
 55. Kalterman, O. G., R. S. Gray, J. Griffin, P. Burstein, J. Insel, J. A. Scarlett, and J. M. Olefsky. Receptor and post‐receptor defects contribute to the insulin resistance in non‐insulin‐dependent diabetes mellitus. J. Clin. Invest. 68: 957–969, 1981.
 56. Kashfi, K., and G. A. Cook. Proteinase treatment of intact hepatic mitochondria has differential effects on inhibition of carnitine palmitoyltransferase by different inhibitors. Biochem. J. 282: 909–914, 1992.
 57. Keda, T., I. Ohtani, K. Fujyama, T. Hoshino, Y. Tanaka, T. Takeuchi, and H. Mashiba. Uptake of β‐hydroxybutyrate in perfused hindquarter of starved and diabetic rats. Metabolism 40: 1287–1291, 1991.
 58. Keller, U., J.‐L. Chiasson, J. E. Lilgenquist, A. D. Cherrington, A. S. Jennings, and O. B. Gofford. The roles of insulin, glucagon, and free fatty acids in the regulation of ketogenesis in dogs. Diabetes 26: 1040–1051, 1977.
 59. Keller, U., P. P. G. Gerber, and W. Stauffacher. Fatty acid independent inhibition of hepatic ketone body production by insulin in humans. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E694–E699, 1988.
 60. Kiorpes, T. C., D. Hoerr, W. Ho, L. E. Weaner, M. G. Inman, and G. F. Tutinler. Identification of 2‐tetradecylglycidyl coenzyme A as the active form of methyl 2‐tetradecylglycidate (methyl palmoxirate) and its characterisation as an irreversible, active site‐directed inhibitor of carnitine palmitoyltransferase A in isolated rat liver mitochondria. J. Biol. Chem. 259: 9750–9755, 1984.
 61. Kispal, G., B. Melegh, I. Alkonyi, and A. Sandor. Enhanced uptake of carnitine by perfused rat liver following starvation. Biochim. Biophys. Acta 896: 96–102, 1987.
 62. Kispal, G., B. Melegh, and A. Sandor. Effect of insulin and glucagon on the uptake of carnitine by perfused rat liver. Biochim. Biophys. Acta 929: 226–228, 1987.
 63. Kolodziej, M. P., P. J. Crilly, C. G. Corstorphine, and V. A. Zammit. Development and characterisation of a polyclonal antibody against rat liver mitochondrial overt carnitine palmitoylcarnitine (CPT I). Distinction of CPT I from CPT II and of isoforms of CPT I in different tissues. Biochem. J. 282: 415–421, 1992.
 64. Kolodziej, M. P., and V. A. Zammit. Sensitivity of inhibition of rat liver mitochondrial outer membrane carnitine palmitoyltransferase by malonyl‐CoA to chemical‐ and temperature‐induced changes in membrane fluidity. Biochem. J. 272: 421–424, 1990.
 65. Koloyianni, M., and R. A. Freedland. Effect of diabetes and time after in vivo insulin administration on ketogenesis and gluconeogenesis in isolated rat hepatocytes. Int. J. Biochem. 22: 159–164, 1990.
 66. Laker, M. E., and P. A. Mayes. Regualtion of 3–hydroxybutyrate formation and secretion of very‐low‐density‐lipoprotein triacylglycerol by perfused livers from fed and starved rats. Biochem. J. 206: 427–430, 1982.
 67. Lee, L. P. K., and I. B. Fritz. Factors controlling ketogenesis by rat liver mitochondria. Can. J. Biochem. 50: 120–127, 1972.
 68. Lewis, G. F., N. M. O'Meara, P. A. Soltys, J. D. Balckman, P. H. Iverius, W. L. Pugh, G. S. Getz, and K. S. Polonsky. Fasting hypertriglyceridemia in non‐insulin‐dependent diabetes mellitus (NIDDM) is an important predictor of post‐prandial lipid and lipoprotein abnormalities. J. Clin. Endocrinol. Metab. 72: 934–944, 1991.
 69. Lewis, G. F., and G. Steiner. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin resistant state. Diabetes Care 19: 390–393, 1996.
 70. Londos, C., D. L. Brasaemle, J. Gruia‐Gray, D. A. Serretnick, C. J. Schultz, D. M. Levin, and A. R. Kimmel. Perilipin: unique proteins associated with intracellular neutral lipid droplets in adipocytes and steroidogenic cells. Biochem. Soc. Trans. 23: 611–615, 1995.
 71. Lopaschuk, G. D., D. Belke, J. Gamble, T. Itoi, and B. O. Schonekess. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim. Biophys. Acta 1213: 263–276, 1994.
 72. Lopaschuk, G. D., D. Belke, J. Gamble, I. Toshiyuki, and B. O. Schonekess. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim. Biophys. Acta 1213: 263–276, 1994.
 73. Lowe, D. M., and P. K. Tubbs. 3‐Hydroxy‐3‐methylglutarylcoenzyme A synthase from ox liver. Purification, molecular and catalytic properties. Biochem. J. 227: 591–599, 1985.
 74. Lowe, D. M., and P. K. Tubbs. Succinylation and inactivation of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase by succinyl‐CoA and its possible relevance to the control of ketogenesis. Biochem. J. 232: 37–42, 1985.
 75. Malaisse, W. J., P. Lebrun, J. Rasschaert, F. Blachier, T. Yilmaz, and A. Sener. Ketone bodies and islet function: 86Rb handling and metabolic data. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E123–E130, 1990.
 76. Malaisse, W. J., P. Lebrun, B. Yaylali, J. Camara, I. Valverde, and A. Sener. Ketone bodies and islet function: 45Ca handling, insulin synthesis, and release. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E117–E122, 1990.
 77. Mascaro, C., E. Acosta, J. A. Ortiz, P. F. Marrero, F. G. Hegardt, and D. Haro. Control of human muscle‐type carnitine palmitoyltransferase I gene transcription by peroxisome proliferatoractivated receptor. J. Biol. Chem. 273: 2560–2563, 1998.
 78. McGarry, J. D.. Disordered metabolism in diabetes: have we underemphasised the fat component? J. Cell. Biochem. 555: 29–38, 1994.
 79. McGarry, J. D.. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258: 766–770, 1992.
 80. McGarry, J. D., and D. W. Foster. Importance of experimental conditions in evaluating the malonyl‐CoA sensitivity of liver carnitine acyltransferase. Studies with fed and starved rats. Biochem. J. 200: 217–223, 1981.
 81. McGarry, J. D., G. I. Leatherman, and D. W. Foster. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl‐CoA. J. Biol. Chem. 253: 4128–4136, 1978.
 82. McGarry, J. D., G. P. Mannaerts, and D. W. Foster. Characteristics of fatty acid oxidation in rat liver homogenates and the inhibitory effect of malonyl‐CoA. Biochim. Biophys. Acta 530: 305–313, 1978.
 83. McGarry, J. D., C. Robles‐Valdes, and D. W. Foster. Role of carnitine in hepatic ketogenesis. Proc. Natl. Acad. Sci. U.S.A. 72: 4385–4388, 1975.
 84. McGivan, J. D., and M. Pastor‐Anglada. Regulatory and molecular aspects of mammalian amino acid transports. Biochem. J. 299: 321–324, 1994.
 85. Moir, A. M. B., and V. A. Zammit. Changes in the properties of cytosolic acetyl‐CoA carboxylase studied in cold‐clamped liver samples from fed, starved and starved‐refed rats. Biochem. J. 272: 511–517, 1990.
 86. Moir, A. M. B., and V. A. Zammit. Monitoring of changes in hepatic fatty acid and glycerolipid metabolism during the starved‐to‐fed transition in vivo. Studies on awake, unrestrained rats. Biochem. J. 289: 49–55, 1993.
 87. Moir, A. M. B., and V. A. Zammit. Rapid switch of hepatic fatty acid metabolism from oxidation to esterification during diurnal feeding of meal‐fed rats correlates with changes in the properties of acetyl‐CoA carboxylase, but not of carnitine palmitoyltransferase I. Biochem. J. 291: 241–246, 1993.
 88. Moir, A. M. B., and V. A. Zammit. Selective labelling of hepatic fatty acids in vivo. Studies on the synthesis and secretion of glycerolipids in the rat. Biochem. J. 283: 145–149, 1992.
 89. Müller, W. A., T. T. Aoki, J.‐P. Flatt, G. L. Blackburn, R. H. Egdahl, and G. F. Cahill, Jr.. Effects of β‐hydroxybutyrate, glycerol and free fatty acid infusions on glucagon and epinephrine secretion in dogs during acute hypoglycaemia. Metabolism 25: 1077–1086, 1976.
 90. Müller, W. A., G. R. Faloona, and R. H. Unger. Hyperglucagonaemia in diabetic ketoacidosis. Its prevalence and significance. Am. J. Med. 54: 52–57, 1973.
 91. Murthy, M. S. R., and S. V. Pande. Malonyl‐CoA binding site and the overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc. Natl. Acad. Sci. U.S.A. 84: 378–382, 1987.
 92. Murthy, M. S. R., and S. V. Pande. Malonyl CoA sensitive and insensitive carnitine palmitoyltransferase activities of microsomes are due to different proteins. J. Biol. Chem. 269: 18283–18286, 1994.
 93. Murthy, M. S. R., and S. V. Pande. Some differences in the properties of carnitine palmitoyltransferase activities of the mitochondrial outer and inner membranes. Biochem. J. 248: 727–733, 1987.
 94. Mynatt, R. L., J. J. Greenshaw, and G. A. Cook. Cholate extracts of mitochondrial outer membrane increase inhibition by malonyl‐CoA of carnitine palmitoyltransferase I by a mechanism involving phospholipids. Biochem. J. 299: 761–767, 1994.
 95. Ochs, R. S.. Evidence for catecholamine activation of α‐ketoglutarate dehydrogenase in isolated hepatocytes. J. Biol. Chem. 259: 13004–13010, 1984.
 96. Olubadewo, J. O., H. G. Wilcox, and M. Heimberg. Differential effects of alanine on ketogenesis and triacyglycerol formation by isolated perfused livers from euthyroid and hyperthyroid rats. Metabolism 34: 1139–1145, 1985.
 97. Ontko, J. A., and M. L. Johns. Evaluation of malonyl‐CoA in the regulation of long‐chain faty acid oxidation in the liver. Evidence for an unidentified regulatory component of the system. Biochem. J. 192: 959–962, 1980.
 98. Pande, S. V., A. K. Bhuiyan, and M. S. R. Murthy. Carnitine palmitoyltransferases: how many and how to discriminate? In: Current Concepts in Carnitine Research, edited by A. L. Carter. Boca Raton, FL: CRC, 1992, p. 165–178.
 99. Park, E. A., R. L. Mynatt, G. A. Cook, and K. Kashfi. Insulin regulates enzyme activity, malonyl CoA sensitivity and mRNA abundance of hepatic carnitine palmitoyltransferase I. Biochem. J. 310: 853–858, 1995.
 100. Parvin, R., and S. V. Pande. Enhancement of mitochondrial carnitine and carnitine acylcarnitine translocase‐mediated transport of fatty acids into liver mitochondria under ketogenic conditions. J. Biol. Chem. 254: 5423–5429, 1979.
 101. Penicaud, L., D. Robin, P. Robin, J. Kande, L. Picon, J. Girard, and P. Ferré. Effect of insulin on the properties of liver carnitine palmitoyltransferase in the starved rat: assessment by the euglycemic hyperinsulinemic clamp. Metabolism 40: 873–876, 1991.
 102. Potts, J. L., S. W. Coppack, R. M. Fisher, S. M. Humphreys, G. F. Gibbons, and K. N. Frayn. Impaired post‐prandial clearance of triacylglycerol‐rich lipoproteins in adipose tissue of obese subjects. Am. J. Physiol. 268 (Endocrinol. Metab. 31): E588–E595, 1995.
 103. Prip‐Buus, C., J. P. Pegorier, P. H. Duée, C. Kohl, and J. Girard. Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl‐CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes. Biochem. J. 26: 409–415, 1990.
 104. Prip‐Buus, C., S. Thumelin, F. Chatelain, J.‐P. Pegorier, and J. Girard. Hormonal and nutritional control of liver fatty acid oxidation and ketogenesis during development. Biochem. Soc. Trans. 23: 500–506, 1995.
 105. Quant, P. A.. Activity and expression of hepatic mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase during the starved‐to‐fed transition. Biochem. Soc. Trans. 18: 994–995, 1990.
 106. Quant, P. A., D. Robin, P. Robin, P. Ferré, M. D. Brand, and J. Girard. Control of hepatic mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase during the foetal/neonatal transition, suckling and weaning in the rat. Eur. J. Biochem. 195: 449–454, 1991.
 107. Quant, P. A., P. K. Tubbs, and M. D. Brand. Glucagon activates mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase in vivo by decreasing the extent of succinylation of the enzyme. Eur. J. Biochem. 187: 169–174, 1990.
 108. Quant, P. A., P. K. Tubbs, and M. D. Brand. Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3‐hydroxy‐3‐methyl‐glutaryl‐CoA synthase activity and decreases succinyl‐CoA content in liver. Biochem. J. 262: 159–164, 1989.
 109. Ramsay, R. R.. A comparison of the malonyl‐CoA sensitive carnitine palmitoyltransferase activities on cytoplasmic substrates and their distribution in mitochondria, peroxisomes and microsomes. Biochem. Life. Sci. Adv. 12: 23–29, 1993.
 110. Rasmussen, J. T., N. J. Faergemen, K. Kristiansen, and J. Knudsen. Acyl‐CoA binding protein (ACBP) can mediate intermembrane acyl‐CoA transport and donate acyl‐CoA for β‐oxidation and glycerolipid synthesis. Biochem. J. 299: 165–170, 1994.
 111. Rasmussen, J. T., J. Rosendal, and J. Knudsen. Interaction of acyl‐CoA binding protein (ACBP) on processes for which acyl‐CoA is a substrate, product or inhibitor. Biochem. J. 292: 907–913, 1993.
 112. Reaven, G. M.. The fourth musketeer—from Alexandre Dumas to Claude Bernard. Diabetologia 38: 3–13, 1995.
 113. Reddi, A. S., G. N. Jyothirmayi, B. De Angelis, O. Frank, and H. Baker. Effect of short‐ and long‐term diabetes on carnitine and myo‐inositol in rats. Comp. Biochem. Physiol. A Physiol. 98: 39–42, 1991.
 114. Robinson, I. N., and V. A. Zammit. Sensitivity of carnitine acyl‐transferase I to malonyl‐CoA inhibition in isolated mitochondria is quantitatively related to hepatic malonyl‐CoA concentration in vivo. Biochem. J. 206: 177–179, 1982.
 115. Sandor, A., J. Cseko, G. Kispal, and I. Alkonyi. Surplus acylcarnitines in the plasma of starved rats derived from the liver. J. Biol. Chem. 265: 22313–22316, 1990.
 116. Sandor, A., G. Kispal, B. Melegh, and I. Alkonyi. Release of carnitine from the perfused rat liver. Biochim. Biophys. Acta 835: 83–91, 1985.
 117. Serra, D., N. Casals, G. Asins, T. Royo, C. J. Ciudad, and F. G. Hegardt. Regulation of mitochondrial 3‐hyroxy‐3‐methylglutaryl‐CoA synthase protein by starvation, fat feeding and diabetes. Arch. Biochem. Biophys. 307: 40–45, 1993.
 118. Siess, E. A., F. M. Fahini, and O. H. Wieland. Decrease by glucagon in hepatic succinyl‐CoA. Biochem. Biophys. Res. Commun. 95: 205–211, 1908.
 119. Singh, B., J. A. Stakkestad, J. Bremer, and B. Borraback. Determination of malonyl‐CoA in rat heart, kidney and liver: a comparison between acetyl‐coenzyme A and butyryl‐coenzyme A as fatty acid synthase in the assay procedure. Anal. Biochem. 138: 107–111, 1984.
 120. Sparks, J. D., and C. E. Sparks. Insulin regulation of triacylglycerolrich lipoprotein synthesis and secretion. Biochim. Biophys. Acta 1215: 9–32, 1994.
 121. Thumelin, S., V. Esser, D. Charvy, M. Kolodziej, V. A. Zammit, J. D. McGarry, J. Girard, and J.‐P. Pegorier. Expression of liver carnitine palmitoyltransferase I and II genes during development in the rat. Biochem. J. 300: 583–587, 1994.
 122. Topping, D. L., and P. A. Mayes. Comparative effects of fructose and glucose on the lipid and carbohydrate metabolism of perfused rat liver. Br. J. Nutr. 36: 113–126, 1976.
 123. Topping, D. L., and P. A. Mayes. Insulin and non‐esterified fatty acids. Acute regulators of lipogenesis in perfused rat liver. Biochem. J. 204: 433–439, 1982.
 124. Vila, M. C., G. Milligan, M. L. Standeart, and R. V. Farese. Insulin activates glycerol‐3‐phosphate acyltransferase (de novo phosphatide acid synthesis) through a phospholipid‐derived mediator. Apparent involvement of Giα and activation of a phospholipase C. Biochemistry 29: 8735–8740, 1990.
 125. Wasserman, D. H., R. M. O'Doherty, and B. A. Zinker. Role of the endocrine pancreas in control of fuel metabolism by the liver during exercise. Int. J. Obes. 19 (Suppl. 4): 522–30, 1995.
 126. Wasserman, D. H., J. S. Spalding, D. B. Lacy, C. A. Colburn, R. E. Goldstein, and A. D. Cherrington. Glucagon is a primary controller of the increments in hepatic glycogenolysis and gluconeogenesis during exercise. Am. J. Physiol. 257, (Endocrinol. Metab. 20): E108–E117, 1989.
 127. Wasserman, D. H., J. S. Spalding, D. P. Spalding, D. B. Lacy, and A. D. Cherrington. Exercise‐induced rise in glucagon and the increase in ketogenesis during prolonged muscular work. Diabetes 38: 799–807, 1989.
 128. Witters, L. A., and C. S. Trasco. Regulation of hepatic free fatty acid metabolism by glucagon and insulin. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol. 6): E23–E29, 1979.
 129. Witters, L. A., T. D. Watts, D. L. Daniels, and J. L. Evans. Insulin stimulates the dephosphorylation and activation of acetyl‐CoA carboxylase. Proc. Natl. Acad. Sci. U.S.A. 85: 5473–5477, 1988.
 130. Wong, S. H., P. J. Nestel, R. P. Trimble, G. B. Storer, R. J. Illman, and D. L. Topping. The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver. Biochim. Biophys. Acta 792: 103–109, 1984.
 131. Woodside, W. F., and M. Heimberg. Effects of anti‐insulin serum, insulin and glucose on output of triglycerides and on ketogenesis by the perfused rat liver. J. Biol. Chem. 251: 13–23, 1976.
 132. Yamaguti, K., H. Kuratsune, Y. Watanabe, M. Takahashi, I. Nakamoto, T. Machii, G. Jacobsson, H. Onoe, K. Matsumura, S. Valind, B. Longstrom, and T. Kitani. Acylcarnitine metabolism during fasting and after refeeding. Biochem. Biophys. Res. Commun. 225: 740–746, 1996.
 133. Zammit, V. A.. Mechanisms of regulation of the partitioning of fatty acids between oxidation and esterification in the liver. Prog. Lipid Res. 23: 39–77, 1984.
 134. Zammit, V. A.. Regulation of hepatic fatty acid metabolism. The activities of mitochondrial and microsomal acyl‐CoA: sn‐glycerol 3‐phosphate O‐acyltransferase and the concentrations of malonyl‐CoA, non‐esterified and esterified carnitine, glycerol 3‐phosphate, ketone bodies and long‐chain acyl‐CoA esters in livers of fed or starved pregnant, lactating and weaned rats. Biochem. J. 198: 75–83, 1981.
 135. Zammit, V. A.. Regulation of ketone body metabolism. A cellular perspective. Diabetes Rev. 2: 132–155, 1994.
 136. Zammit, V. A.. Role of insulin in hepatic fatty acid partitioning: emerging concepts. Biochem. J. 314: 1–14, 1996.
 137. Zammit, V. A.. Time‐dependence of inhibition of carnitine palmitoyltransferase I by malonyl‐CoA in mitochondria isolated from livers of fed or starved rats. Evidence for transition of the enzyme between states of low and high affinity for malonyl‐CoA. Biochem. J. 218: 379–386, 1984.
 138. Zammit, V. A., A. Beis, and E. A. Newsholme. The role of 3‐oxo acid‐CoA transferase in the regulation of ketogenesis in the liver. FEBS Lett. 103: 212–215, 1979.
 139. Zammit, V. A., and C. G. Corstorphine. Altered release of carnitine palmitoyltransferase activity by digitonin from liver mitochondria of rats in different physiological states. Biochem. J. 230: 389–394, 1986.
 140. Zammit, V. A., C. G. Corstorphine, and S. R. Gray. Changes in the ability of malonyl‐CoA to inhibit carnitine palmitoyltransferase I activity and to bind to rat liver mitochondria during incubation in vitro. Differences in binding at 0°C and 37°C with a fixed concentration of malonyl‐CoA. Biochem. J. 222: 335–42, 1984.
 141. Zammit, V. A., C. G. Corstorphine, M. P. Kolodziej, and F. Fraser. Lipid molecular order in liver mitochondrial outer membranes, and sensitivity of carnitine palmitoyltransferase I to malonyl‐CoA. Lipids 33: 371–376, 1998.
 142. Zammit, V. A., and R. A. Easom. Regulation of hepatic HMG‐CoA reductase in vivo by reversible phosphorylation. Biochim. Biophys. Acta 927: 223–228, 1987.
 143. Zammit, V. A., F. Fraser, and C. G. Corstorphine. Regulation of mitochondrial outer membrane carnitine palmitoyltransferase (CPT I): role of membrane topology. Adv. Enzyme Regul. 37: 295–317, 1997.
 144. Fraser, F., C. G. Corstorphine, N. T. Price, and V. A. Zammit. Evidence that carnitine palmitoyltransferase 1 (CPT‐I) is expressed in micronomes and peroxisomes of rat liver. Distinct immunoreactivity of the N‐terminal domain of the microsomal protein. FEBS Letters 446: 69–74. 1999.
 145. Zammit, V. A., and A. M. B. Moir. Monitoring the partitioning of hepatic fatty acids in vivo: keeping track of control. Trends Biochem. Sci. 19: 313–317, 1994.
 146. Zammit, V. A., D. J. Lankester, A. M. Brown and B‐S. Park. Insulin stimulates triacylgyerol secretion by perfused livers from fed rats but inhibits it in livers from fasted or insulin‐deficient rats. Eur. J. Biochem. 263: 859–864, 1999.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Victor A. Zammit. Regulation of Ketogenesis in Liver. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 659-673. First published in print 2001. doi: 10.1002/cphy.cp070221