A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians

146

Skeletal muscle is a major mass peripheral tissue that accounts for ϳ40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces ␤-adrenergic receptor (␤-AR)-mediated adaptive thermogenesis. ␤-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30 -60 min of ␤-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase ␥3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and ␤-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.Obesity and fat deposition are primarily controlled by food intake and energy expenditure. Obesity has been linked to the development of heart disease, cancer, and stroke, the top three causes of death in the United States, and has recently been recognized by the World Health Organization as one of the top 10 global health problems. Moreover, obesity leads to metabolic syndrome X, a disorder that includes elevated levels of triglycerides and low density lipoprotein (bad) cholesterol, low levels of high density lipoprotein (good) cholesterol, impaired fasting glucose, and hypertension (2). These are cardiovascular risk factors for diseases such as atherosclerosis and type II diabetes. More than 65% of United States adults are overweight, and Ͼ30% of adults (greater than 61 million people) are clinically obese (1, 2).Diet, lifestyle, metabolism, and genetics are the most significant factors in controlling weight. Current obesity therapies perform modestly and are aimed at central appetite suppression and reduced fat absorption. Recent research su...

Section: Figmentioning

confidence: 48%

Nur77 Regulates Lipolysis in Skeletal Muscle Cells

Maxwell

Cleasby

Harding

et al. 2005

146

“…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).…”

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

Self Cite

268

229

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...

“…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 abnormalities of lipid and glucose metabolism (13) and with altered susceptibility to the metabolic syndrome (14) and diabetes-associated coronary disease (15).…”

mentioning

confidence: 99%

Luminal Lipid Regulates CD36 Levels and Downstream Signaling to Stimulate Chylomicron Synthesis

Tran

Poirier

Clement

et al. 2011

Self Cite

112

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...