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...

Nonalcoholic fatty liver disease (NAFLD) affects about 30% of the general population in the United States and includes a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Significant insight has been gained into our understanding of the pathogenesis of NALFD; however the key metabolic aberrations underlying lipid accumulation in hepatocytes and the progression of NAFLD remain to be elucidated. Accumulating and emerging evidence indicate that hepatic mitochondria play a critical role in the development and pathogenesis of steatosis and NAFLD. Here, we review studies that document a link between the pathogenesis of NAFLD and hepatic mitochondrial dysfunction with particular focus on new insights into the role of impaired fatty acid oxidation, the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuins in development and progression of NAFLD.

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

The membrane glycoprotein CD36 binds nanomolar concentrations of long chain fatty acids (LCFA) and is highly expressed on the luminal surface of enterocytes. CD36 deficiency reduces chylomicron production through unknown mechanisms. In this report, we provide novel insights into some of the underlying mechanisms. Our in vivo data demonstrate that CD36 gene deletion in mice does not affect LCFA uptake and subsequent esterification into triglycerides by the intestinal mucosa exposed to the micellar LCFA concentrations prevailing in the intestine. In rodents, the CD36 protein disappears early from the luminal side of intestinal villi during the postprandial period, but only when the diet contains lipids. This drop is significant 1 h after a lipid supply and associates with ubiquitination of CD36. Using CHO cells expressing CD36, it is shown that the digestion products LCFA and diglycerides trigger CD36 ubiquitination. In vivo treatment with the proteasome inhibitor MG132 prevents the lipid-mediated degradation of CD36. In vivo and ex vivo, CD36 is shown to be required for lipid activation of ERK1/2, which associates with an increase of the key chylomicron synthesis proteins, apolipoprotein B48 and microsomal triglyceride transfer protein. Therefore, intestinal CD36, possibly through ERK1/2-mediated signaling, is involved in the adaptation of enterocyte metabolism to the postprandial lipid challenge by promoting the production of large triglyceride-rich lipoproteins that are rapidly cleared in the blood. This suggests that CD36 may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks.CD36 (also known as fatty acid translocase) is a transmembrane glycoprotein expressed in many tissues. It is a multifunctional protein homologous to scavenger receptor class B, type I. CD36 facilitates uptake of long chain fatty acids (LCFA) 2 in cardiomyocytes (1) and adipocytes (2, 3) and that of oxidized LDL by macrophages (4). CD36 is involved in platelet aggregation by binding thrombospondin and collagen (5), phagocytosis of apoptotic cells by macrophages (6), and the cytoadhesion of erythrocytes infected with Plasmodium falciparum (7). In addition, CD36 has recently been shown to play a role in taste perception of dietary fatty acid on the tongue by triggering a cell signaling cascade (8 -10). Deletion of CD36 in mice highlighted the importance of this protein for optimal utilization of dietary lipids. Significant impairment in the uptake of LCFA by skeletal muscle, heart, and adipose tissues was shown (2). Insulin-and exercise-dependent translocation of CD36 from an intracellular pool to the sarcolemna was documented and postulated to increase the muscle efficiency by allowing adaptive changes in LCFA uptake and utilization (11, 12). Finally, CD36-deficient mice exhibit a loss of the spontaneous preference for lipid-rich foods and a decrease of orosensory-mediated rise in digestive secretions (8, 9). In humans, variants in the CD36 gene have been associated with abnormalit...

Recommended CitationDrover, Victor A.; Ajmal, Mohammad; Nassir, Fatiha; Davidson, Nicholas O.; Nauli, Andromeda M.; Sahoo, Daisy; Tso, Patrick; and Abumrad, Nada A., ,"CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood." The Journal of Clinical Investigation. 115,5. 1290-1297. (2005