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

Abstract

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...

Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops

“…Interestingly, micelle binding to both transporters was positively correlated to chain length and unsaturation. This is in line with the concept of longchain fatty acids being CD36 ligands ( 37 ). Moreover, accordingly to our SPR data showing that free OA and DHA were SR-BI ligands, mice overexpressing SR-BI at the A key fi nding is that these structures mimicking mixed micelles, i.e., including various lipids and lipid digestion products, are necessary for optimal binding to both lCD36 and lSR-BI.…”

Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption

“…mice on a C57BL/6 background were produced and characterized as described earlier ( 33 ( 36 ). As expected, 4 h after the gavage of a bolus containing radiolabeled cholesterol and sitostanol, much more cholesterol than sitostanol is present in the intestinal wall.…”

“…A weighed sample of liver was analyzed in a similar fashion. Plasma samples were prepared from the blood and analyzed for radioactive sterols by liquid scintillation counting and for cholesterol levels by an enzymatic assay ( 33 ).…”

“…The class B scavenger receptors cluster determinant 36 (CD36) ( 29 ) and scavenger receptor class B, type 1 (SR-BI) ( 30 ), which have established lipid transport capabilities, have been known for a decade or more to be located in the BBM and can potentially mediate cholesterol uptake into the BBM. Indeed, experiments with mice in which these genes are deleted have demonstrated that SR-BI is important for the absorption of ␤ -carotene ( 31 ) and vitamin E ( 32 ), and CD36 is important for the absorption of very long chain fatty acids ( 33 ). However, there is no effect on cholesterol absorption of deleting either SR-BI ( 31,34,35 ) or CD36 ( 36 ), although both receptors have been shown to facilitate the transport of cholesterol into cells ( 31,37,38 ).…”

Fatty Acid- and Cholesterol Transporter Protein Expression along the Human Intestinal Tract

“…FAT/CD36 in particular is important for very long-chain (VLC) FA (more than 18 carbon atoms) metabolism, since intestinal VLCFA uptake was completely abolished in CD36 2/2 mice [55]. Lobo et al [56] described that in humans, FAT/CD36 protein was restricted to duodenal and jejunal epithelium.…”