Is Membrane Transport of FFA Mediated by Lipid, Protein, or Both?

Kampf, J. Patrick; Kleinfeld, Alan M.

doi:10.1152/physiol.00011.2006

Cited by 81 publications

(34 citation statements)

References 66 publications

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“…23). Much of this debate is fuelled by the fact that many of the common fatty acids such as 16:0 and 18:1 have relatively high diffusion rates (compared with VLCFAs), which can mask facilitated processes (24).…”

Section: Discussionmentioning

confidence: 99%

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

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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Section: Discussionmentioning

confidence: 99%

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

143

113

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“…Nevertheless, a recent study demonstrated that Acsl3 has a higher substrate affi nity for oleic acid than longer-chain FAs ( 41 ). Furthermore, neither the paralogous acsl3b transcript nor the acsl5 transcript were induced in Tg ( fabp2:EGFP-nr1h3 ) enterocytes, arguing that Acsl3a activity is uniquely induced by intestinal Lxra activation of contention ( 51 ). Taken together, these studies in larvae, adults, and isolated enterocytes indicate that overexpression of Lxra in the intestine drives storage of absorbed FAs in cytoplasmic lipid droplets.…”

Section: Intestinal Overexpression Of Lxra Delays Lipid Absorptionmentioning

confidence: 97%

Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Cruz-García

Schlegel

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org of atherosclerosis ( 2 ). The most widely used treatment for atherosclerosis is statin drugs, which potently inhibit 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis ( 3 ). Nevertheless, statins do not fully mitigate cardiovascular risk. Recent epidemiological investigations reveal that postprandial (nonfasting) plasma lipid levels are a major determinant of cardiovascular risk because they refl ect the persistence of highly atherogenic remnant lipoprotein particles in the circulation ( 4 ). Statin drugs do not modulate the abundance or atherogenicity of remnant lipoprotein particles ( 5 ).Elucidation of the regulatory events controlling the pace of entry of ingested lipids into the blood stream in chylomicrons might afford the opportunity to blunt postprandial hyperlipidemia. Human jejunal biopsies ( 6 ), prolonged, label-free lipid droplet imaging of live loops of mouse intestine ( 7 ), and fl uorescent lipid probe-based visualization of intestinal lipid droplets in zebrafi sh larvae ( 8 ) have revealed that a substantial fraction of absorbed lipids remain in the enterocyte for many hours following a meal. These fi ndings suggest that there is an intrinsic mechanism for delaying, in part, transit of absorbed lipids. The molecular mechanism accounting for this hours-long retention of absorbed lipids in the intestine is not known.Liver X receptors (Lxrs) are nuclear receptor transcription factors that regulate energy metabolism through engaging specifi c metabolite substrates such as oxysterols and then altering the expression of diverse, but functionally integrated genes ( 9, 10 ). Lxrs are central inducers of cholesterol catabolism ( 9, 10 ). Known direct target genes of Lxr transactivation include factors involved in reverse cholesterol transport; lipoprotein modifi cation; cholesterol Atherosclerotic cardiovascular disease is the leading cause of death worldwide ( 1 ). Elevated serum cholesterol is a major causal risk factor for development and progression

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“…However, in recent years, there has been a fundamental shift in our understanding, and it is now widely recognized that long chain fatty acids cross the plasma membrane via a protein-mediated mechanism (for reviews, see Refs. [1][2][3]. A number of fatty acid transporters have been identified, including fatty acid translocase/CD36 (FAT/CD36), plasma membrane-associated fatty acid binding proteins (FABPpm), and a family of fatty acid transport proteins (FATP1-6) 5 (for reviews, see Refs.…”

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confidence: 99%

Greater Transport Efficiencies of the Membrane Fatty Acid Transporters FAT/CD36 and FATP4 Compared with FABPpm and FATP1 and Differential Effects on Fatty Acid Esterification and Oxidation in Rat Skeletal Muscle

Nickerson

Alkhateeb

Benton

et al. 2009

Journal of Biological Chemistry

168

144

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In selected mammalian tissues, long chain fatty acid transporters (FABPpm, FAT/CD36, FATP1, and FATP4) are co-expressed. There is controversy as to whether they all function as membrane-bound transporters and whether they channel fatty acids to oxidation and/or esterification. Among skeletal muscles, the protein expression of FABPpm, FAT/CD36, and FATP4, but not FATP1, correlated highly with the capacities for oxidative metabolism (r > 0.94), fatty acid oxidation (r > 0.88), and triacylglycerol esterification (r > 0.87). We overexpressed independently FABPpm, FAT/CD36, FATP1, and FATP4, within a normal physiologic range, in rat skeletal muscle, to determine the effects on fatty acid transport and metabolism. Independent overexpression of each fatty acid transporter occurred without altering either the expression or plasmalemmal content of other fatty acid transporters. All transporters increased fatty acid transport, but FAT/CD36 and FATP4 were 2.3-and 1.7-fold more effective than FABPpm and FATP1, respectively. Fatty acid transporters failed to alter the rates of fatty acid esterification into triacylglycerols. In contrast, all transporters increased the rates of long chain fatty acid oxidation, but the effects of FABPpm and FAT/CD36 were 3-fold greater than for FATP1 and FATP4. Thus, fatty acid transporters exhibit different capacities for fatty acid transport and metabolism. In vivo, FAT/CD36 and FATP4 are the most effective fatty acid transporters, whereas FABPpm and FAT/CD36 are key for stimulating fatty acid oxidation.

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Is Membrane Transport of FFA Mediated by Lipid, Protein, or Both?

Cited by 81 publications

References 66 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

Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids

Greater Transport Efficiencies of the Membrane Fatty Acid Transporters FAT/CD36 and FATP4 Compared with FABPpm and FATP1 and Differential Effects on Fatty Acid Esterification and Oxidation in Rat Skeletal Muscle

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