A null mutation in the scavenger receptor gene CD36 was created in mice by targeted homologous recombination. These mice produced no detectable CD36 protein, were viable, and bred normally. A significant decrease in binding and uptake of oxidized low density lipoprotein was observed in peritoneal macrophages of null mice as compared with those from control mice. CD36 null animals had a significant increase in fasting levels of cholesterol, nonesterified free fatty acids, and triacylglycerol. The increase in cholesterol was mainly within the high density lipoprotein fraction, while the increase in triacylglycerol was within the very low density lipoprotein fraction. Null animals had lower fasting serum glucose levels when compared with wild type controls. Uptake of 3 H-labeled oleate was significantly reduced in adipocytes from null mice. However, the decrease was limited to the low ratios of fatty acid:bovine serum albumin, suggesting that CD36 was necessary for the high affinity component of the uptake process. The data provide evidence for a functional role for CD36 in lipoprotein/fatty acid metabolism that was previously underappreciated.Scavenger receptors are integral membrane glycoproteins, distinct from the classic low density lipoprotein (LDL) 1 receptor, that mediate binding and uptake of native and modified lipoproteins by macrophages (1-8). There are at least two major classes of mammalian monocyte/macrophage scavenger receptors, SR-A and SR-B, based on molecular sequence and protein structural homology (1, 2, 9 -11). Scavenger receptors have broad ligand specificity and may have evolved from the primitive immune system as pattern recognition molecules, which are able to recognize common structural motifs on microbial surfaces (1,6,(12)(13)(14)(15)(16)(17). They also function in the recognition and clearance of damaged, senescent, or apoptotic cells before lysis, tissue damage, and inflammation can ensue (11, 18 -21) and in the modulation of cytokine release and host immune responses (14,15,22). Scavenger receptors may be important in the pathogenesis of atherosclerosis, since there is significant evidence in support of the hypothesis that uptake of oxidatively modified LDL by monocytes/macrophages is one of the key early events in lesion development (23-26).The class A receptors, which are expressed on liver sinusoidal endothelial and Kupffer cells (27)(28)(29), and monocytes/ macrophages (9, 10, 30) result from an alternative splice from a single gene (31, 32). SR-AI/II are trimeric, integral membrane glycoprotein receptors for oxidized LDL, acetylated LDL, and other anionic ligands including polyinosinic acid and maleylated albumin (5, 9, 10, 33-35). Monocytes/macrophages isolated from a null mouse carrying a mutation in the class A receptors showed partial loss in the ability to bind and internalize oxidized LDL (ϳ30%) (36), and a lack of murine SR-AI/II receptors in the context of an atherogenic environment was partially protective against the formation of atherogenic lesions, decreasing lesion...
The effects of dexamethasone on lipid accumulation by human monocyte-derived macrophages were investigated. Preincubation of macrophages with dexamethasone for a period of 16-20 h resulted in a reproducible increase (3.5-fold) in the incorporation of oleate into cholesteryl esters. The effect was specific because no alterations were observed in oleate incorporation into triglycerides or phospholipids. Measurement of cellular cholesteryl esters indicated a fourfold increase after preincubation with dexamethasone. This increase was mediated by opposite effects on synthesis and breakdown of these lipids. Dexamethasone produced a 60% increase in activity of the enzyme acyl-CoA: cholesterol O-acyltransferase (ACAT), active in synthesis of cholesteryl esters, and a 40% decrease in that of neutral cholesteryl esterase, active in cholesteryl ester breakdown. The increased ACAT activity appeared to reflect increased mRNA for the enzyme. The effects of dexamethasone on cholesteryl ester accumulation by macrophages reached statistical significance at a concentration of 100 nM. They were dose dependent, and saturation was observed at around 1 microM. The effects were significant at low concentrations of cholesterol in the medium. At high-medium cholesterol, there was a large cholesterol-induced increase in ACAT activity that obscured most of the effect of dexamethasone. In general, the data suggest that high glucocorticoid levels enhance lipid accumulation by macrophages and thus would have an atherogenic action that is independent of serum cholesterol.
To study the acute effect of dietary docosahexaenoic acid (DHA, C 22:6 ) on the expression of adipocyte determination and differentiation-dependent factor 1 (ADD1) mRNA in pig tissues, weaned, crossbred pigs (28 d of age) were fed with either 10% (on as-fed basis) tallow (high stearic acid), soybean oil (high linoleic acid), or high DHA algal oil for 2 d. The plasma and liver DHA reflected the composition of the diet. The adipose tissue and skeletal muscle DHA did not reflect the diet in the short term feeding. The results also showed that the diet containing 10% algal DHA oil significantly decreased the total plasma cholesterol (39%) and triacylglycerol (TG; 46%) in the pigs. Soybean oil significantly decreased plasma TG (13.7%; p<0.05), but did not have an effect on plasma cholesterol. The data indicate that different dietary fatty acid compositions have different effects on plasma lipids. The ADD1 mRNA was decreased (p<0.05) in the liver of DHA oil-treated pigs compared with the tallow-treated pigs. The diets did not have significant effect on the ADD1 mRNA in adipose tissue. Addition of algal DHA oil in the diet increased acyl CoA oxidase (ACO) mRNA concentration in the liver, suggesting that dietary DHA treatment increases peroxisomal fatty acid oxidation in the liver. However, dietary soybean oil supplementation did not affect mRNA concentrations of ADD1 or ACO in the tissues of pigs. Because ADD1 increases the expression of genes associated with lipogenesis, and ACO is able to promote fatty acid oxidation, feeding DHA oil may change the utilization of fatty acids through changing the expression of ADD1 and ACO. Therefore, feeding pigs with high DHA may lead to lower body fat deposition.
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