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

CD36 mediates the transfer of fatty acids (FAs) across the plasma membranes of muscle and adipose cells, thus playing an important role in regulating peripheral FA metabolism in vivo. In the proximal intestine, CD36 is localized in abundant quantities on the apical surface of epithelial cells, a pattern similar to that of other proteins implicated in the uptake of dietary FAs. To define the role of CD36 in the intestine, we examined FA utilization and lipoprotein secretion by WT and CD36-null mice in response to acute and chronic fat feeding. CD36-null mice given a fat bolus by gavage or fed a high-fat diet accumulated neutral lipid in the proximal intestine, which indicated abnormal lipid processing. Using a model in which mice were equipped with lymph fistulae, we obtained evidence of defective lipoprotein secretion by directly measuring lipid output. The secretion defect appeared to reflect an impaired ability of CD36-null enterocytes to efficiently synthesize triacylglycerols from dietary FAs in the endoplasmic reticulum. In the plasma of intact mice, the reduced intestinal lipid secretion was masked by slow clearance of intestine-derived lipoproteins. The impaired clearance occurred despite normal lipoprotein lipase activity and likely reflected feedback inhibition of the lipase by FAs due to their defective removal from the plasma. We conclude that CD36 is important for both secretion and clearance of intestinal lipoproteins. CD36 deficiency results in hypertriglyceridemia both in the postprandial and fasting states and in humans may constitute a risk factor for diet-induced type 2 diabetes and cardiovascular disease.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments.

Genetic variants in the fatty acid (FA) translocase FAT/CD36 associate with abnormal postprandial lipids and influence risk for the metabolic syndrome. CD36 is abundant on apical enterocyte membranes in the proximal small intestine, where it facilitates FA uptake and FA-initiated signaling. We explored whether CD36 signaling influences FA-mediated secretion of cholecystokinin (CCK) and secretin, peptides released by enteroendocrine cells (EECs) in the duodenum/jejunum, which regulate events important for fat digestion and homeostasis. CD36 was immunodetected on apical membranes of secretin- and CCK-positive EECs and colocalized with cytosolic granules. Intragastric lipid administration to CD36 mice released less secretin (-60%) and CCK (-50%) compared with wild-type mice. Likewise, diminished secretin and CCK responses to FA were observed with CD36 intestinal segments in vitro, arguing against influence of alterations in fat absorption. Signaling mechanisms underlying peptide release were examined in STC-1 cells stably expressing human CD36 or a signaling-impaired mutant (CD36K/A). FA stimulation of cells expressing CD36 (vs. vector or CD36K/A) released more secretin (3.5- to 4-fold) and CCK (2- to 3-fold), generated more cAMP (2- to 2.5-fold), and enhanced protein kinase A activation. Protein kinase A inhibition (H-89) blunted secretin (80%) but not CCK release, which was reduced (50%) by blocking of calmodulin kinase II (KN-62). Coculture of STC-1 cells with Caco-2 cells stably expressing CD36 did not alter secretin or CCK release, consistent with a minimal effect of adjacent enterocytes. In summary, CD36 is a major mediator of FA-induced release of CCK and secretin. These peptides contribute to the role of CD36 in fat absorption and to its pleiotropic metabolic effects.