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Febbraio, Maria; Guy, Ella; Coburn, Chris T.; Knapp, F. F.; Beets, A.L.; Abumrad, Nada A.; Silverstein, Roy L.

doi:10.1023/a:1020515210972

Cited by 79 publications

(13 citation statements)

References 51 publications

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“…Little is known about the mechanics of LCFA transport by FAT/CD36, even at the plasma membrane. It is possible that FAT/CD36 acts as an acceptor or docking protein, either handing LCFAs off to other proteins (36,37), or simply assisting their movement through lipophobic environments. Conversely, it is possible that FAT/CD36 acts as a carrier protein, delivering cytosolic LCFAs to the mitochondria for further processing.…”

Section: Discussionmentioning

confidence: 99%

A Novel Function for Fatty Acid Translocase (FAT)/CD36

Campbell

Tandon

Woldegiorgis

et al. 2004

Journal of Biological Chemistry

226

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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.

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Section: Discussionmentioning

confidence: 99%

A Novel Function for Fatty Acid Translocase (FAT)/CD36

Campbell

Tandon

Woldegiorgis

et al. 2004

Journal of Biological Chemistry

226

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“…CD36 has been shown to bind long-chain fatty acids (2,3) and to facilitate their transfer into the cell (4,5). Deficiency or overexpression of the protein is associated with alterations in uptake and metabolism of longchain fatty acids in rodents (4,6,7). In humans, Cd36 deficiency (8) and polymorphisms in the Cd36 gene (9) are associated with abnormalities in FA clearance (10,11), insulin responsiveness (11,12), and lipoprotein metabolism (13,14).…”

Section: Cd36 or Fatty Acid Translocase (Fat)mentioning

confidence: 99%

CD36 Is Important for Fatty Acid and Cholesterol Uptake by the Proximal but Not Distal Intestine

Nassir

Wilson

Han

et al. 2007

Journal of Biological Chemistry

274

229

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CD36, a membrane protein that facilitates fatty acid uptake, is highly expressed in the intestine on the luminal surface of enterocytes. Cd36 null (Cd36 ؊/؊ ) mice exhibit impaired chylomicron secretion but no overall lipid absorption defect. Because chylomicron production is most efficient proximally we examined whether CD36 function is important for proximal lipid absorption. CD36 levels followed a steep decreasing gradient along three equal-length, proximal to distal intestinal segments (S1-S3). Enterocytes isolated from the small intestines of Cd36 ؊/؊ mice, when compared with wild type counterparts, exhibited reduced uptake of fatty acid (50%) and cholesterol (60%) in S1. The high affinity fatty acid uptake component was missing in Cd36 ؊/؊ cells. Fatty acid incorporation into triglyceride and triglyceride secretion were also reduced in Cd36 ؊/؊ S1 enterocytes. In vivo, proximal absorption was monitored using mass spectrometry from oleic acid enrichment of S1 lipids, 90 min (active absorption) and 5 h (steady state) after intragastric olive oil (70% triolein). Oleate enrichment was 50% reduced at 90 min in Cd36 ؊/؊ tissue consistent with defective uptake whereas no differences were measured at 5 h. In Cd36 ؊/؊ S1, mRNA for L-fabp, Dgat1, and apoA-IV was reduced. Protein levels for FATP4, SR-BI, and NPC1L1 were similar, whereas those for apoB48 and apoA-IV were significantly lower. A large increase in NPC1L1 was observed in Cd36 ؊/؊ S2 and S3. The findings support the role of CD36 in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, whereas CD36-independent mechanisms predominate in distal segments. CD36 or fatty acid translocase (FAT)3 is an 88-kDa transmembrane protein with broad specificity. Its ligands include long-chain fatty acids, native and oxidized lipoproteins, thrombospondin-1, collagen, amyloid ␤, and malaria-infected erythrocytes, recently reviewed in Ref. 1. CD36 has been shown to bind long-chain fatty acids (2, 3) and to facilitate their transfer into the cell (4, 5). Deficiency or overexpression of the protein is associated with alterations in uptake and metabolism of longchain fatty acids in rodents (4, 6, 7). In humans, Cd36 deficiency (8) and polymorphisms in the Cd36 gene (9) are associated with abnormalities in FA clearance (10, 11), insulin responsiveness (11, 12), and lipoprotein metabolism (13, 14). As a result CD36 has been implicated in the etiology of diabetes and atherosclerosis (14, 15).Consistent with its role in FA uptake CD36 is very abundant in the heart, skeletal muscle, adipose tissue (16), and the capillary endothelium (17). The protein is also highly expressed in the small intestine (16,18,19) and localizes to the apical membrane of villi enterocytes (19). Expression levels and localization strongly suggest a function in lipid absorption but this could not be documented in previous studies by us and others (20 -22). Administration of a lipid load to Cd36-deficient mice did not identify alterations in the blood appearance of intes...

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“…Overexpression of PPARγ in liver of PPARα null mice induced the expression of lipogenic genes, leading to hepatic steatosis [14]. CD36, a membrane receptor capable of uptaking modified forms of low-density lipoproteins (LDL) and fatty acids from circulation [15], [16], has been identified as a direct target of PPARγ in liver [17]. While expression of an activated form of PPARδ in the adipose tissues of transgenic mice was shown to activate fat metabolism and produce lean mice that are resistant to obesity induced either genetically or by a high fat diet [18].…”

Section: Introductionmentioning

confidence: 99%

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

Zhang

Wei

et al. 2013

PLoS ONE

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The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene.

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Untitled

Cited by 79 publications

References 51 publications

A Novel Function for Fatty Acid Translocase (FAT)/CD36

A Novel Function for Fatty Acid Translocase (FAT)/CD36

CD36 Is Important for Fatty Acid and Cholesterol Uptake by the Proximal but Not Distal Intestine

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

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