CD36 Is Important for Chylomicron Formation and Secretion and May Mediate Cholesterol Uptake in the Proximal Intestine

Nauli, Andromeda M.; Nassir, Fatiha; Zheng, Shuqin; Yang, Qing; Lo, Chun–Min; VonLehmden, Sarah B.; Lee, Dana; Jandacek, Ronald J.; Abumrad, Nada A.; Tso, Patrick

doi:10.1053/j.gastro.2006.08.012

Cited by 169 publications

(179 citation statements)

References 34 publications

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“…CD36 is expressed in epithelial cells of the small intestine along the gastro-colic and crypt-to-villus axes in a pattern paralleling that of other proteins implicated in FA uptake such as intestinal and liver FA-binding proteins (5)(6)(7). In addition, we have shown that CD36 is important for chylomicron production and acute FA uptake in the proximal intestine (8,9). * This work was supported, in whole or in part, by National Institutes of Health Grants DK060022 (to N. A.…”

supporting

confidence: 54%

CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice

Drover

Nguyen

Bastie

et al. 2008

Journal of Biological Chemistry

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143

113

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The intestine has an extraordinary capacity for fatty acid (FA) absorption. Numerous candidates for a protein-mediated mechanism of dietary FA absorption have been proposed, but firm evidence for this process has remained elusive. Here we show that the scavenger receptor CD36 is required both for the uptake of very long chain FAs (VLCFAs) in cultured cells and the absorption of dietary VLCFAs in mice. We found that the fraction of CD36-dependent saturated fatty acid association/absorption in these model systems is proportional to the FA chain length and specific for fatty acids and fatty alcohols containing very long saturated acyl chains. Moreover, intestinal VLCFA absorption is completely abolished in CD36-null mice fed a high fat diet, illustrating that the predominant mechanism for VLCFA absorption is CD36-dependent. Together, these findings represent the first direct evidence for protein-facilitated FA absorption in the intestine and identify a novel therapeutic target for the treatment of diseases characterized by elevated VLCFA levels.In typical Western diets, the bulk of the calories exist in the chemical form of triacylglycerols (TAGs) 4 that consist of glycerol esterified to three fatty acid (FA) molecules. Once consumed, the FAs are liberated from TAG via pancreatic enzymes and are quantitatively absorbed by the body for energy, storage, and other cellular processes. The mechanism(s) responsible for the absorption of dietary FAs have not been well characterized. Given the extraordinary capacity of the gut for FA absorption, it seems likely that diffusion plays a major role in this process. The most common fatty acids in a typical diet are the long chain FAs palmitate (16:0) and oleate (18:1), which have relatively high rates of simple diffusion in model membrane systems (reviewed in Ref. 1).Unlike the long chain FAs, saturated very long chain FAs (VLCFAs) are much less soluble in aqueous environments, and the diffusion rates are much lower. In mixtures of vesicles and albumin (which model FA delivery to peripheral cells such as adipocytes), VLCFAs partition more favorably into phospholipid bilayers compared with long chain FAs (2). In addition, the dissociation of saturated VLCFAs from model vesicles is 10 5 -10 6 -fold slower than the dissociation of long chain FAs (3). This combination of preferential partitioning and slow dissociation suggests that protein-based mechanisms may be required for efficient absorption and utilization of VLCFAs in peripheral tissues in vivo.In contrast to peripheral absorption, VLCFA absorption in the intestine is essentially an unstudied field. The only direct experimentation to date was published in 1963 wherein Fields and Gatt (4) determined that intragastric or intraduodenal [ 14 C]lignoceric acid (24:0) was absorbed in the rat intestine and appeared in the lymph primarily in the neutral glyceride fraction (i.e. triacylglycerol). Since then, intestinal fatty acid absorption has been primarily studied using only long chain FAs and often employed indirect measures su...

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supporting

confidence: 54%

CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice

Drover

Nguyen

Bastie

et al. 2008

Journal of Biological Chemistry

Self Cite

143

113

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“…Chylomicron size is highly dependent on expression levels of a few LBPs and apolipoproteins. For instance, FAT/CD36 knockout mice secrete smaller chylomicrons than wild-type mice (30), and the induction of intestinal apoA-IV has been reported to lead to larger particles (27,31). According to these data, the fat-mediated increase of genes encoding FAT/CD36 and apoA-IV might produce large chylomicrons rapidly hydrolyzed by LPL.…”

Section: Discussionmentioning

confidence: 99%

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

Petit

Arnould́

Martin³

et al. 2007

Journal of Lipid Research

119

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The effects of chronic fat overconsumption on intestinal physiology and lipid metabolism remain elusive. It is unknown whether a fat-mediated adaptation to lipid absorption takes place. To address this issue, mice fed a high-fat diet (40%, w/w) were refed or not a control diet (3%, w/w) for 3 additive weeks. Despite daily lipid intake 7.7-fold higher than in controls, fecal lipid output remained unchanged in mice fed the triglyceride (TG)-rich diet. In situ isolated jejunal loops revealed greater [1-14 C]linoleic acid uptake without TG accumulation in mucosa, suggesting an increase in lipid absorption capacity. Induction both in intestinal mitotic index and in the expression of genes involved in fatty acid uptake, trafficking, and lipoprotein synthesis was found in high-fat diet mice. These changes were lipid-mediated, in that they were fully abolished in mice refed the control diet. A lipid load test performed in the presence or absence of the LPL inhibitor tyloxapol showed a sustained blood TG clearance in fat-fed mice likely attributable to intestinal modulation of LPL regulators (apolipoproteins C-II and C-III). These data demonstrate that a chronic high-fat diet greatly affects intestinal physiology and body lipid use in the mouse.-Petit, V., L. Arnould, P. Martin, M-C. Monnot, T. Pineau, P. Besnard, and I. Niot. Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse. J. Lipid Res.

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“…Additionally, overexpression of CD36 in COS-7 cells has been shown to enhance cholesterol uptake from micellar substrates (184). In another study, CD36-null mice showed a significant reduction in cholesterol transport from the intestinal lumen to the lymphatic system (133). Decreased cholesterol uptake has been shown in brush-border membrane vesicles prepared from the proximal (but not distal) intestine of SR-BI-KO mice (184) and in brush-border membrane vesicles and Caco-2 cells preincubated with antibodies to SR-BI (71).…”

Section: Cholesterolmentioning

confidence: 99%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

663

484

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Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phospholipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the diet, contributing 90 -95% of the total energy derived from dietary fat. Dietary fats also include phospholipids (PLs), sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen is phosphatidylcholine (PC), which is derived mostly from bile (10 -20 g/day in humans) but also from the diet (ϳ1-2 g/day). The predominant dietary sterols are cholesterol (mostly of animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not absorbed by humans under physiological conditions.Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of drugs capable of reducing the risk of lipid-associated disorders, including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also explored key issues of absorption, e.g., the uptake of the products of lipid hydrolysis by enterocytes (the epithelial cells lining the walls of the intestinal lumen) and their transport to intracellular compartments, where fatty acids and sterols are...

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CD36 Is Important for Chylomicron Formation and Secretion and May Mediate Cholesterol Uptake in the Proximal Intestine

Abstract: Background & Aims-Studies are aimed to determine the role of CD36 in intestinal lipid absorption.

Cited by 169 publications

References 34 publications

CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice

CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

Intestinal lipid absorption

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