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Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis

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ABSTRACT

Several proteins have been implicated in fatty acid (FA) transport by enterocytes including the scavenger receptor CD36 (SR‐B2), the scavenger receptor B1 (SR‐B1) a member of the CD36 family and the FA transport protein 4 (FATP4). Here, we review the regulation of enterocyte FA uptake and its function in lipid absorption including prechylomicron formation, assembly and transport. Emphasis is given to CD36, which is abundantly expressed along the digestive tract of rodents and humans and has been the most studied. We also address the pleiotropic functions of CD36 that go beyond lipid absorption and metabolism to include recent evidence of its impact on intestinal homeostasis and barrier maintenance. Areas of progress involving contribution of membrane phospholipid remodeling and of cytosolic FA‐binding proteins, FABP1 and FABP2 to fat absorption will be covered. © 2018 American Physiological Society. Compr Physiol 8:493‐507, 2018.

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Figure 1. Figure 1. Lipid absorption from epithelial cells (enterocytes) and chylomicron secretion in lymphatic vessels (lacteals). (A) During absorption of dietary lipids, the FA and MAGs are released from micelles in the lumen (indicated by 1, top panel) and both enter at the apical side of intestinal epithelial cells, also called enterocytes that line the luminal side of the small intestine. TAGs are synthesized in the ER of enterocytes (2, middle panel) from the absorbed FA and MAG and exit the ER en route to the Golgi in the PCTVs. The PCTVs mature in the Golgi (3, middle panel) and are then released by the enterocytes as TAG‐enriched chylomicron particles (4, bottom panel) that enter the lymphatic vessels located inside intestinal villi, called lacteals (5 bottom panel). (B) Once in the lacteals, chylomicrons are transported via the lymph through mesenteric lymph nodes and collecting lymphatic vessels ultimately reaching the thoracic duct, which drains into the venous circulation at the level of the left subclavian vein.
Figure 2. Figure 2. FA uptake is reduced in enterocytes from the proximal intestine of Cd36−/‐ mice but its contribution to net intestinal FA uptake is small. (A) FA uptake includes saturable and nonsaturable components. The graph illustrates the high affinity saturable FA uptake component that is mediated by CD36 (). The blue bar shows the range of unbound FA concentrations (<10 nmol/L) present in the blood during feeding and fasting. At this range of concentrations, the saturable CD36‐mediated component (dashed orange line) contributes the major part of FA uptake from the circulation to peripheral tissues such as muscle and adipose tissues. In the intestine, the relative contribution of FA transport to total uptake by enterocytes is likely to be small since the concentration of free FA released from micelles (green bar) is estimated to be 1000‐fold higher as compared to that in the blood; FA transfer by diffusion or other mechanisms would constitute the major route of FA uptake by enterocytes (see section “Role of phospholipid remodeling in intestinal FA absorption”). (B) Time course of OA uptake by enterocytes from WT (filled squares) and Cd36‐null mice (open squares). Cells were incubated with [3H]‐oleate for the indicated times (0–30 min) and uptake was stopped using cold Krebs‐Ringer‐Hepes bicarbonate (KRH) buffer. Cells collected by centrifugation through a Ficoll layer were analyzed for associated radioactivity. In these experiments, the FA was used bound to bovine serum albumin at a FA:BSA ratio of 2 (), which associates with nanomole per liter concentrations of unbound FA. In the intestine, the saturable component of FA uptake would function in FA sensing early during absorption and exerts a regulatory role in initiating chylomicron production (see section “Chylomicron formation”) and enteroendocrine secretion of CCK and secretin to facilitate absorption (see section “Other function of CD36”).
Figure 3. Figure 3. Model of CD36‐mediated FA transport. Proposed mechanism of FA transfer by CD36 modeled based on CD36’s crystal structure (). CD36 is a transmembrane receptor with a large ectodomain and two transmembrane segments ending in two short cytoplasmic tails (orange cylinders). Crystallized CD36 was found in complex with long chain FA (palmitic and stearic acids) (). The FA (FA skeleton shown) is thought to dock within a surface hydrophobic cavity where the carboxylic tail of the FA is in proximity of lysine 164 (K164 is highlighted in green) (). The cavity would lead the FA to an internal tunnel inside the protein (translucent cylinder) that empties at the membrane bilayer (). Interaction with K164 could position the FA to favor its access to the tunnel (). Green: K164 residue; Red: hydrophobic residues; Blue: hydrophilic residues; cylinder indicates the location of the internal tunnel inside the CD36 receptor. The figure shows the structure of OA interacting with K164 residue.
Figure 4. Figure 4. Prechylomicron formation and budding. Assembly of prechylomicrons occurs in the lumen of the ER. Prechylomicrons are packaged into specialized PCTVs that bud off the ER membrane and move to the cis‐Golgi where they fuse with the Golgi membrane to deliver the prechylomicron cargo into the Golgi lumen. Note that PCTVs bud from the ER membrane in the absence of COPII, which are required for vesicular transport of nascent protein such as apoproteins from ER to Golgi. After processing in the Golgi, a separate vesicular system transports mature chylomicrons to the basolateral membrane.
Figure 5. Figure 5. Role of CD36 and FABP1 in budding of the ER prechylomicron particle for transfer to the Golgi. Newly absorbed FA and MAG are endocytosed at the enterocyte apical membrane in caveolin‐1 containing endocytic vesicles (CEV) that also carry CD36 (step 1). The FA and MAG are reesterified into TAG to generate lipid droplets in the ER lumen and in the cytosol and both merge to form the prechylomicron particle in the ER (see section on prechylomicron formation). Budding of the prechylomicron is thought to require FABP1 binding to the ER, which is induced by the following sequence of events. The CEV contains protein kinase zeta (PKC‐ζ) and lyso‐phosphatidylcholine (LPC) on its surface and PKC‐ζ is activated by LPC. Upon activation, PKC‐ζ elutes from the CEV into the cytosol where it phosphorylates its substrate Sar1b (step 2). Phosphorylation of Sarb1 releases FABP1 from a cytosolic heteroquatromeric protein complex where it is sequestered together with other proteins (Sec13, and SVIP) (step 3). Released FABP1 binds to the ER and together with CD36, apoB48, and VAMP7 promotes budding from the ER of the PCTVs (step 4) for its transfer to the Golgi (step 5). Once the PCTV reaches the Golgi, it becomes tethered and subsequently fuses with the Golgi membrane delivering its chylomicron cargo into the lumen. The chylomicron matures in the Golgi where additional apoproteins are added (ApoA‐1 and ApoA‐IV) and then is released across the basolateral membrane of the enterocyte to be transported into the lymph (see Fig. 1).


Figure 1. Lipid absorption from epithelial cells (enterocytes) and chylomicron secretion in lymphatic vessels (lacteals). (A) During absorption of dietary lipids, the FA and MAGs are released from micelles in the lumen (indicated by 1, top panel) and both enter at the apical side of intestinal epithelial cells, also called enterocytes that line the luminal side of the small intestine. TAGs are synthesized in the ER of enterocytes (2, middle panel) from the absorbed FA and MAG and exit the ER en route to the Golgi in the PCTVs. The PCTVs mature in the Golgi (3, middle panel) and are then released by the enterocytes as TAG‐enriched chylomicron particles (4, bottom panel) that enter the lymphatic vessels located inside intestinal villi, called lacteals (5 bottom panel). (B) Once in the lacteals, chylomicrons are transported via the lymph through mesenteric lymph nodes and collecting lymphatic vessels ultimately reaching the thoracic duct, which drains into the venous circulation at the level of the left subclavian vein.


Figure 2. FA uptake is reduced in enterocytes from the proximal intestine of Cd36−/‐ mice but its contribution to net intestinal FA uptake is small. (A) FA uptake includes saturable and nonsaturable components. The graph illustrates the high affinity saturable FA uptake component that is mediated by CD36 (). The blue bar shows the range of unbound FA concentrations (<10 nmol/L) present in the blood during feeding and fasting. At this range of concentrations, the saturable CD36‐mediated component (dashed orange line) contributes the major part of FA uptake from the circulation to peripheral tissues such as muscle and adipose tissues. In the intestine, the relative contribution of FA transport to total uptake by enterocytes is likely to be small since the concentration of free FA released from micelles (green bar) is estimated to be 1000‐fold higher as compared to that in the blood; FA transfer by diffusion or other mechanisms would constitute the major route of FA uptake by enterocytes (see section “Role of phospholipid remodeling in intestinal FA absorption”). (B) Time course of OA uptake by enterocytes from WT (filled squares) and Cd36‐null mice (open squares). Cells were incubated with [3H]‐oleate for the indicated times (0–30 min) and uptake was stopped using cold Krebs‐Ringer‐Hepes bicarbonate (KRH) buffer. Cells collected by centrifugation through a Ficoll layer were analyzed for associated radioactivity. In these experiments, the FA was used bound to bovine serum albumin at a FA:BSA ratio of 2 (), which associates with nanomole per liter concentrations of unbound FA. In the intestine, the saturable component of FA uptake would function in FA sensing early during absorption and exerts a regulatory role in initiating chylomicron production (see section “Chylomicron formation”) and enteroendocrine secretion of CCK and secretin to facilitate absorption (see section “Other function of CD36”).


Figure 3. Model of CD36‐mediated FA transport. Proposed mechanism of FA transfer by CD36 modeled based on CD36’s crystal structure (). CD36 is a transmembrane receptor with a large ectodomain and two transmembrane segments ending in two short cytoplasmic tails (orange cylinders). Crystallized CD36 was found in complex with long chain FA (palmitic and stearic acids) (). The FA (FA skeleton shown) is thought to dock within a surface hydrophobic cavity where the carboxylic tail of the FA is in proximity of lysine 164 (K164 is highlighted in green) (). The cavity would lead the FA to an internal tunnel inside the protein (translucent cylinder) that empties at the membrane bilayer (). Interaction with K164 could position the FA to favor its access to the tunnel (). Green: K164 residue; Red: hydrophobic residues; Blue: hydrophilic residues; cylinder indicates the location of the internal tunnel inside the CD36 receptor. The figure shows the structure of OA interacting with K164 residue.


Figure 4. Prechylomicron formation and budding. Assembly of prechylomicrons occurs in the lumen of the ER. Prechylomicrons are packaged into specialized PCTVs that bud off the ER membrane and move to the cis‐Golgi where they fuse with the Golgi membrane to deliver the prechylomicron cargo into the Golgi lumen. Note that PCTVs bud from the ER membrane in the absence of COPII, which are required for vesicular transport of nascent protein such as apoproteins from ER to Golgi. After processing in the Golgi, a separate vesicular system transports mature chylomicrons to the basolateral membrane.


Figure 5. Role of CD36 and FABP1 in budding of the ER prechylomicron particle for transfer to the Golgi. Newly absorbed FA and MAG are endocytosed at the enterocyte apical membrane in caveolin‐1 containing endocytic vesicles (CEV) that also carry CD36 (step 1). The FA and MAG are reesterified into TAG to generate lipid droplets in the ER lumen and in the cytosol and both merge to form the prechylomicron particle in the ER (see section on prechylomicron formation). Budding of the prechylomicron is thought to require FABP1 binding to the ER, which is induced by the following sequence of events. The CEV contains protein kinase zeta (PKC‐ζ) and lyso‐phosphatidylcholine (LPC) on its surface and PKC‐ζ is activated by LPC. Upon activation, PKC‐ζ elutes from the CEV into the cytosol where it phosphorylates its substrate Sar1b (step 2). Phosphorylation of Sarb1 releases FABP1 from a cytosolic heteroquatromeric protein complex where it is sequestered together with other proteins (Sec13, and SVIP) (step 3). Released FABP1 binds to the ER and together with CD36, apoB48, and VAMP7 promotes budding from the ER of the PCTVs (step 4) for its transfer to the Golgi (step 5). Once the PCTV reaches the Golgi, it becomes tethered and subsequently fuses with the Golgi membrane delivering its chylomicron cargo into the lumen. The chylomicron matures in the Golgi where additional apoproteins are added (ApoA‐1 and ApoA‐IV) and then is released across the basolateral membrane of the enterocyte to be transported into the lymph (see Fig. 1).
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Teaching Material

V. Cifarelli, N. A. Abumrad. Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis. Compr Physiol. 8: 2018, 493-507.

Didactic Synopsis

The information provided in this review should facilitate teaching students about our current knowledge related to key proteins involved in uptake and absorption of dietary fatty acids in the small intestine. The following specific topics might be suitable for graduate or advanced undergraduate levels:

  • Absorption of dietary fatty acid (FA) across the brush border membrane of enterocyte in the proximal small intestine can occur through passive diffusion and/or can be mediated by specific transport proteins.
  • Remodeling of membrane phospholipid might be important for diffusion of FA in enterocytes.
  • Scavenger receptor CD36 (SR-B2) is a brush-border membrane protein that facilitates FA uptake and FA processing in enterocytes of rodents and human.
  • The component of uptake mediated by CD36 is a small fraction of net FA uptake by the small intestine but it plays a regulatory role by priming the organ for packaging the absorbed lipid and secreting it as lipoproteins.
  • Absorbed lipids are packaged into lipoprotein particles called chylomicrons in the enterocyte. Generation of chylomicrons requires several steps including pre-chylomicron formation and assembly in the endoplasmic reticulum (ER), prechylomicron transport from the ER to the Golgi for maturation, and chylomicron exocytosis from the enterocyte into the interstitium to enter the lymphatic system.
  • CD36 and liver fatty acid binding protein 1, FABP1, play a crucial role in chylomicron formation, assembly and trafficking from ER to Golgi.
  • The FA receptor CD36 has pleiotropic functions. In addition to its role in absorption and chylomicron formation, it mediates secretion of intestinal peptides and is important for maintenance of intestinal homeostasis and epithelial barrier integrity.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching. Figure 1–Figure 5

Figure 1. Lipid absorption from epithelial cells and chylomicron secretion in the lymphatic system. This figure illustrates the mechanisms that regulate absorption of dietary fats in the small intestine. (A) After a meal, dietary fats or lipids are digested into fatty acids (FAs) and monoacylglycerides (MAGs) and emulsified into micelles starting in the mouth and stomach. Once in the lumen of the intestine, FA and MAGs are released from the micelles and enter intestinal epithelial cells through the apical side (indicated by 1 in top panel). Triglycerides (TAG) are synthesized from FAs in the ER (2, middle panel) and then released as PCTV from the ER en route to the Golgi (step 3). The PCTV mature in the Golgi and are then released by the enterocytes as TAG enriched chylomicron particles (4, bottom panel). This step is necessary to ensure transport of dietary lipids from the intestine into the bloodstream. Given their size, newly formed chylomicrons cannot directly enter the bloodstream but they are released from the enterocyte basolateral membrane into the intestinal lymphatic vessels or lacteals (4, bottom panel). Once in the lacteals, chylomicrons are transported via the lymph into peripheral tissues (5, bottom panel). (B) Chylomicrons are exocytosed from the basolateral membrane of enterocytes into the intestinal lacteals. The chylomicron-rich lymph runs through mesenteric lymph nodes and collecting lymphatic vessels and ultimately empties into the thoracic duct. The lymph enters the circulation at the level left subclavian vein. From there the chylomicron supply the tissues with fat absorbed from the diet.

Figure 2. Fatty acid uptake is reduced in enterocytes from the proximal intestine of Cd36−/− mice but its contribution to net intestinal FA uptake is small. Teaching points: (A) Graph illustrating the high affinity of the saturable FA uptake mediated by CD36 (1). The blue bar shows the range of unbound FA concentrations (<10 nmol/L) present in the blood during feeding and fasting. The saturable CD36-mediated component (dashed orange line) contributes the major part of FA uptake from the circulation to peripheral tissues such as muscle and adipose tissues. The relative contribution of FA transport to total uptake by enterocytes is likely to be small since the concentration of free FA released from micelles is estimated to be 1000-fold higher (in the low micromolar); FA transfer by diffusion or other mechanisms would constitute the major route of FA uptake by enterocytes. The saturable component would function early during absorption and exert a regulatory role in initiating chylomicron production and facilitating absorption. (B) Time course of oleic acid uptake by enterocytes from WT (filled squares) and Cd36-null mice (open squares). Cells were incubated with [3H]-oleate for the indicated times (0–30 min) and uptake was stopped using cold Krebs-Ringer-Hepes bicarbonate (KRH) buffer. Cells collected by centrifugation through a Ficoll layer were analyzed for associated radioactivity. The FA was used bound to bovine serum albumin at a FA:BSA ratio of 2 (107), which associates with nanomole per liter concentrations of unbound FA. In the intestine, the saturable component of FA uptake would function in FA sensing early during absorption and exert a regulatory role in initiating chylomicron production and enteroendocrine secretion of CCK and secretin facilitating absorption.

Figure 3. Model of CD36-mediated FA transport. This figure illustrates the proposed mechanism of FA transfer by CD36 modeled based on CD36’s crystal structure (67, 109). CD36 is a transmembrane receptor with a large ectodomain, two transmembrane segments ending in two short cytoplasmic tails (orange cylinders). Crystallized CD36 was found in complex with long chain FA (palmitic and stearic acids) (67). The FA (FA skeleton shown in figure) is thought to dock within a surface hydrophobic cavity where the carboxylic tail of the FA is in proximity of lysine 164 (K164 is highlighted in green) (80). The cavity would lead the FA to an internal tunnel inside the protein (translucent cylinder) that empties at the membrane bilayer (80). Interaction with K164 could position the FA to favor its access to the tunnel (80, 118). Green: K164 residue; Red: hydrophobic residues; Blue: hydrophilic residues; cylinder indicates the location of the internal tunnel inside the CD36 receptor. The figure includes the structure of the fatty acid oleic acid interacting with the K164 residue.

Figure 4. Prechylomicron formation and budding. Teaching point of this figure is that the ER in the enterocyte uses distinct transport vesicles for chylomicrons as compared to nascent proteins. There are several differences in these two transport vesicle systems. First, PCTV formation is intermittent and coincides with dietary fat intake whereas protein vesicle continually ferries new proteins to the Golgi for cellular distribution and use (i.e., ApoAI). Second, only ATP, and not GTP, is required for prechylomicron transport. Third, PCTVs bud from the ER membrane in the absence of COPII, which are required for vesicular transport of nascent protein from ER to Golgi. After processing in the Golgi, a separate vesicular system transports mature chylomicrons to the basolateral membrane.

Figure 5. Model for budding of the ER prechylomicron and its transfer to the Golgi. This figure provides detailed information on the mechanisms involved in the budding of pre-chylomicrons. The process begins with the formation of caveolin-1-coated endosomal vesicles (CEV) formed at the level of the apical membrane to mediate the endocytosis of newly absorbed FA and MAG through interaction with receptor CD36 (step 1). The FA and MAG are reesterified into TAG to generate lipid droplets in the ER lumen and in the cytosol and both merge to form the pre-chylomicron particle in the ER (see section on prechylomicron formation). Additional players located on CEV surface are PKC-ζ and lyso-PC (LPC). Presence of LPC is necessary to activate PKC-ζ. Upon activation, PKC-ζ elutes from the CEV into the cytosol, enabling it to phosphorylate its substrate Sar1b (step 2). This releases FABP1 from being sequestered in a cytosolic heteroquatromeric protein complex (with Sec13, and SVIP) by Sar1b (step 3). The monomeric FABP1 can bind to the ER and together with CD36, apoB48 and VAMP7 promotes budding of the pre-chylomicron transport vesicle (PCTV) from the ER (step 4) for transfer to the Golgi (step 5). Once the PCTV reaches the Golgi, it becomes tethered and subsequently fuses with the Golgi membrane delivering its chylomicron cargo into the lumen. The chylomicron matures in the Golgi where additional apolipoproteins are added (ApoA-1 and ApoA-IV) and then is released across the basolateral membrane of the enterocyte to be transported into the lymph (see Figure 1).


Related Articles:

Enterocyte Lipid Absorption and Secretion
Luminal Events in Gastrointestinal Lipid Digestion
Metabolism of lipids in chylomicrons and very low‐density lipoproteins
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Vincenza Cifarelli, Nada A. Abumrad. Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis. Compr Physiol 2018, 8: 493-507. doi: 10.1002/cphy.c170026