Luminal Lipid Regulates CD36 Levels and Downstream Signaling to Stimulate Chylomicron Synthesis

Abstract

The membrane glycoprotein CD36 binds nanomolar concentrations of long chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. CD36 deficiency reduces chylomicron production through unknown mechanisms. In this report, we provide novel insights into some of the underlying mechanisms. Our in vivo data demonstrate that CD36 gene deletion in mice does not affect LCFA uptake and subsequent esterification into triglycerides by the intestinal mucosa exposed to the micellar LCFA concentrations prevailing in the intestine. In rodents, the CD36 protein disappears early from the luminal side of intestinal villi during the postprandial period, but only when the diet contains lipids. This drop is significant 1 h after a lipid supply and associates with ubiquitination of CD36. Using CHO cells expressing CD36, it is shown that the digestion products LCFA and diglycerides trigger CD36 ubiquitination. In vivo treatment with the proteasome inhibitor MG132 prevents the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 is shown to be required for lipid activation of ERK1/2, which associates with an increase of the key chylomicron synthesis proteins, apolipoprotein B48 and microsomal triglyceride transfer protein. Therefore, intestinal CD36, possibly through ERK1/2-mediated signaling, is involved in the adaptation of enterocyte metabolism to the postprandial lipid challenge by promoting the production of large triglyceride-rich lipoproteins that are rapidly cleared in the blood. This suggests that CD36 may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks.CD36 (also known as fatty acid translocase) is a transmembrane glycoprotein expressed in many tissues. It is a multifunctional protein homologous to scavenger receptor class B, type I. CD36 facilitates uptake of long chain fatty acids (LCFA) 2 in cardiomyocytes (1) and adipocytes (2, 3) and that of oxidized LDL by macrophages (4). CD36 is involved in platelet aggregation by binding thrombospondin and collagen (5), phagocytosis of apoptotic cells by macrophages (6), and the cytoadhesion of erythrocytes infected with Plasmodium falciparum (7). In addition, CD36 has recently been shown to play a role in taste perception of dietary fatty acid on the tongue by triggering a cell signaling cascade (8 -10). Deletion of CD36 in mice highlighted the importance of this protein for optimal utilization of dietary lipids. Significant impairment in the uptake of LCFA by skeletal muscle, heart, and adipose tissues was shown (2). Insulin-and exercise-dependent translocation of CD36 from an intracellular pool to the sarcolemna was documented and postulated to increase the muscle efficiency by allowing adaptive changes in LCFA uptake and utilization (11, 12). Finally, CD36-deficient mice exhibit a loss of the spontaneous preference for lipid-rich foods and a decrease of orosensory-mediated rise in digestive secretions (8, 9). In humans, variants in the CD36 gene have been associated with abnormalit...

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

“…Overall, our findings support an important role of CD36 in the handling of dietary lipids in humans and are consistent with data in CD36-null mice showing defective CM metabolism and persistently high levels of CM remnants (9,(23)(24)(25). Elevated CM remnant levels were reported in small cohorts of CD36-deficient subjects (9,26,27).…”

“…Evidence from CD36-null mouse models and CD36-deficient humans suggests that the protein regulates postprandial TGs and cholesterol metabolism. In mice, CD36 deficiency increases cholesterol levels, impairs CM secretion into the lymph, and delays postprandial TG clearance (9,(23)(24)(25). A similar phenotype is found in CD36-deficient subjects who were reported to have increased CM remnants and cholesterol levels (9,26,27).…”

CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

“…5C ). Palmitate oxidation by ( 7,21 ), neurotransmitter release in taste buds ( 3 ), and FA-induced cholecystokinin and secretin release from enteroendocrine cells ( 8 ). The current study shows that CD36 plays a role in hepatic VLDL secretion since its deletion reduces TG and apoB output by the liver.…”

“…Recent data documented the role of CD36-mediated signaling in FA metabolism via affecting cellular calcium ( 18,19 ) and the MAPK ERK1/2 pathway ( 20,21 ). An important consequence of CD36's ability to signal to intracellular calcium was its regulation of the formation and release of prostaglandins (PG) ( 20 ), bioactive compounds with pleiotropic effects that include inhibition of hepatic VLDL secretion ( 22,23 ).…”

DHA attenuates postprandial hyperlipidemia via activating PPARα in intestinal epithelial cells

“…4 ), which is involved in FA transport in intestinal epithelial cells of DHA-rich oil-fed mice. Cd36 is thought to be involved in regulating chylomicron production ( 43,44 ). Interestingly, Cd36 knockout mice showed both fasting and postprandial hyperlipidemia and have been used as a model of postprandial hyperlipidemia ( 45 ).…”