Research Notes: Genes - Fatty Acid Translocase (FAT)/CD36

Clin Genet. 2006 Jan.
CD36 expression and its relationship with obesity in blood cells from people with and without Prader-Willi syndrome.
Webb T, Whittington J, Holland AJ, Soni S, Boer H, Clarke D, Horsthemke B.
Section of Medical and Molecular Genetics, University of Birmingham, Birmingham, UK.

Although Prader-Willi syndrome (PWS) has been linked to the loss of function of imprinted genes in 15q11q13, very little is known about the pathogenesis. Using quantitative real-time PCR, we have confirmed the previous observation of an abnormality of CD36 expression in cells with maternal uniparental disomy 15, obtained from a proband with mosaicism for PWS, by demonstrating reduced expression levels in blood cells from a series of non-mosaic probands with PWS. Furthermore, we have extended these observations to show that CD36 expression in a non-PWS population is inversely correlated with body mass index but that this correlation does not hold in PWS. CD36 which maps to 7q11.2 is the first gene outside the 15q11q13 region whose level of expression appears to be reduced in people with PWS. Low CD36 expression levels in PWS point to an abnormal control of lipid and glucose homeostasis which may explain the insatiable hunger in these patients.

Gastroenterology. 2006 Oct.
CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine.
Nauli AM, Nassir F, Zheng S, Yang Q, Lo CM, Vonlehmden SB, Lee D, Jandacek RJ, Abumrad NA, Tso P.
Department of Pathology and Laboratory Medicine, Genome Research Institute, University of Cincinnati College of Medicine, 2120 Galbraith Road, Cincinnati, OH, USA.

Background and aims: Studies are aimed to determine the role of CD36 in intestinal lipid absorption. Methods: Knock-out (KO) and wild-type (WT) lymph fistula mice were used to study fatty acids (FA) and cholesterol uptake, and chylomicron formation and secretion. Uptake of FA and cholesterol was studied by using sucrose polybehenate and fecal dual isotope methods, respectively. Results: The CD36 KO exhibited significant accumulation of dietary cholesterol in the intestinal lumen at the end of 6-hour lipid infusion and significant reduction of dietary cholesterol transport into the lymph. Fecal dual isotope studies, however, did not show any significant difference in cholesterol uptake, suggesting that given sufficient time, the KO intestine could compensate for the reduced cholesterol uptake observed in the acute lymph fistula studies. Recovery of dietary FA in the intestinal lumen was comparable between WT and KO, consistent with the sucrose polybehenate study. However, the KO mice accumulated more, albeit not significantly, dietary triacylglycerols in the intestine, followed by a significant reduction in lymphatic transport. The ratio of intestinal dietary triacylglycerols to FA was not higher in WT than KO, arguing against impaired lipid esterification. It is rather a deficiency in the formation and secretion of chylomicrons, as supported by the significantly less apolipoprotein B-48 and the smaller, albeit not significantly, lipoprotein particles secreted into the lymph of the KO. Conclusions: CD36 may play an important role in chylomicron formation and secretion and may also facilitate cholesterol uptake in the proximal intestine.

Am J Physiol Endocrinol Metab. 2006 Mar.
Identification of fatty acid translocase on human skeletal muscle mitochondrial membranes: essential role in fatty acid oxidation.
Bezaire V, Bruce CR, Heigenhauser GJ, Tandon NN, Glatz JF, Luiken JJ, Bonen A, Spriet LL.
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.

Fatty acid translocase (FAT/CD36) is a transport protein with a high affinity for long-chain fatty acids (LCFA). It was recently identified on rat skeletal muscle mitochondrial membranes and found to be required for palmitate uptake and oxidation. Our aim was to identify the presence and elucidate the role of FAT/CD36 on human skeletal muscle mitochondrial membranes. We demonstrate that FAT/CD36 is present in highly purified human skeletal mitochondria. Blocking of human muscle mitochondrial FAT/CD36 with the specific inhibitor sulfo-N-succimidyl-oleate (SSO) decreased palmitate oxidation in a dose-dependent manner. At maximal SSO concentrations (200 muM) palmitate oxidation was decreased by 95% (P<0.01), suggesting an important role for FAT/CD36 in LCFA transport across the mitochondrial membranes. SSO treatment of mitochondria did not affect mitochondrial octanoate oxidation and had no effect on maximal and submaximal carnitine palmitoyltransferase I (CPT I) activity. However, SSO treatment did inhibit palmitoylcarnitine oxidation by 92% (P<0.001), suggesting that FAT/CD36 may be playing a role downstream of CPT I activity, possibly in the transfer of palmitoylcarnitine from CPT I to carnitine-acylcarnitine translocase. These data provide new insight regarding human skeletal muscle mitochondrial fatty acid (FA) transport, and suggest that FAT/CD36 could be involved in the cellular and mitochondrial adaptations resulting in improved and/or impaired states of FA oxidation.

J Biol Chem. 2004 Aug 27.
A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria.
Campbell SE, Tandon NN, Woldegiorgis G, Luiken JJ, Glatz JF, Bonen A.
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
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Fatty acid translocase (FAT)/CD36 is a long chain fatty acid transporter present at the plasma membrane, as well as in intracellular pools of skeletal muscle. In this study, we assessed the unexpected presence of FAT/CD36 in both subsarcolemmal and intermyofibril fractions of highly purified mitochondria. Functional assessments demonstrated that the mitochondria could bind (14)C-labeled palmitate, but could only oxidize it in the presence of carnitine. However, the addition of sulfo-N-succinimidyl oleate, a known inhibitor of FAT/CD36, resulted in an 87 and 85% reduction of palmitate oxidation in subsarcolemmal and intermyofibril fractions, respectively. Further studies revealed that maximal carnitine palmitoyltransferase I (CPTI) activity in vitro was inhibited by succinimidyl oleate (42 and 48% reduction). Interestingly, CPTI immunoprecipitated with FAT/CD36, indicating a physical pairing. Tissue differences in mitochondrial FAT/CD36 protein follow the same pattern as the capacity for fatty acid oxidation (heart >> red muscle > white muscle). Additionally, chronic stimulation of hindlimb muscles (7 days) increased FAT/CD36 expression and also resulted in a concomitant increase in mitochondrial FAT/CD36 content (46 and 47% increase). Interestingly, with acute electrical stimulation of hindlimb muscles (30 min), FAT/CD36 expression was not altered, but there was an increase in the mitochondrial content of FAT/CD36 compared with the non-stimulated control limb (35 and 37% increase). Together, these data suggest a role for FAT/CD36 in mitochondrial long chain fatty acid uptake and demonstrate system flexibility to match FAT/CD36 mitochondrial content with an increased capacity for fatty acid oxidation, possibly involving translocation of FAT/CD36 to the mitochondria.

Am J Clin Nutr. 2003 Feb.
A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle.
Cameron-Smith D, Burke LM, Angus DJ, Tunstall RJ, Cox GR, Bonen A, Hawley JA, Hargreaves M.
School of Health Sciences, Deakin University, Burwood, Victoria, Australia.

Background: Dietary fatty acids may be important in regulating gene expression. However, little is known about the effect of changes in dietary fatty acids on gene regulation in human skeletal muscle. Objective: The objective was to determine the effect of altered dietary fat intake on the expression of genes encoding proteins necessary for fatty acid transport and beta-oxidation in skeletal muscle. Design: Fourteen well-trained male cyclists and triathletes with a mean (+/- SE) age of 26.9 +/- 1.7 y, weight of 73.7 +/- 1.7 kg, and peak oxygen uptake of 67.0 +/- 1.3 mL x kg(-1) x min(-1) consumed either a high-fat diet (HFat: > 65% of energy as lipids) or an isoenergetic high-carbohydrate diet (HCho: 70-75% of energy as carbohydrate) for 5 d in a crossover design. On day 1 (baseline) and again after 5 d of dietary intervention, resting muscle and blood samples were taken. Muscle samples were analyzed for gene expression [fatty acid translocase (FAT/CD36), plasma membrane fatty acid binding protein (FABPpm), carnitine palmitoyltransferase I (CPT I), beta-hydroxyacyl-CoA dehydrogenase (beta-HAD), and uncoupling protein 3 (UCP3)] and concentrations of the proteins FAT/CD36 and FABPpm. Results: The gene expression of FAT/CD36 and beta -HAD and the gene abundance of FAT/CD36 were greater after the HFat than after the HCho diet (P < 0.05). Messenger RNA expression of FABPpm, CPT I, and UCP-3 did not change significantly with either diet. Conclusions: A rapid and marked capacity for changes in dietary fatty acid availability to modulate the expression of mRNA-encoding proteins is necessary for fatty acid transport and oxidative metabolism. This finding is evidence of nutrient-gene interactions in human skeletal muscle.