Abstract
CD36 facilitates oxidized low density lipoprotein uptake and is implicated in development of atherosclerotic lesions. CD36 also binds unmodified high and very low density lipoproteins (HDL, VLDL) but its role in the metabolism of these particles is unclear. Several polymorphisms in the CD36 gene were recently shown to associate with serum HDL cholesterol. To gain insight into potential mechanisms for these associations we examined HDL metabolism in CD36 null (CD36−/−) mice. Feeding CD36−/− mice a high cholesterol diet significantly increased serum HDL, cholesterol and phospholipids, as compared to wild type mice. HDL apolipoproteins apoA-I and apoA-IV were increased and shifted to higher density HDL fractions suggesting altered particle maturation. Clearance of dual-labeled HDL was unchanged in CD36−/− mice and cholesterol uptake from HDL or LDL by isolated CD36−/− hepatocytes was unaltered. However, CD36−/− hepatocytes had higher cholesterol and phospholipid efflux rates. In addition, expression and secretion of apoA-I and apoA-IV were increased reflecting enhanced PXR. Similar to hepatocytes, cholesterol and phospholipid efflux were enhanced in CD36−/− macrophages without changes in protein levels of ABCA1, ABCG1 or SR-B1. However, biotinylation assays showed increased surface ABCA1 localization in CD36−/− cells. In conclusion, CD36 influences reverse cholesterol transport and hepatic ApoA-I production. Both pathways are enhanced in CD36 deficiency, increasing HDL concentrations, which suggests the potential benefit of CD36 inhibition.
Highlights
Cluster of Differentiation 36 (CD36) is an 88 kD transmembrane glycoprotein and type B scavenger receptor with a range of lipid ligands that includes long chain fatty acids (FA)[1] and native or modified lipoproteins[2]
In this report we describe the impact of CD36 deficiency in mice on High density lipoproteins (HDL) metabolism and examine the mechanisms involved
The initial report on CD36 deficient mice fed a chow diet with 4% fat described a modest increase (30%) of plasma cholesterol and HDL as compared to WT mice[11] but increased HDL were not noted in other studies[5,29]
Summary
Cluster of Differentiation 36 (CD36) is an 88 kD transmembrane glycoprotein and type B scavenger receptor with a range of lipid ligands that includes long chain fatty acids (FA)[1] and native or modified lipoproteins[2]. Cholesterol uptake by macrophages from oxidized low density lipoproteins (ox-LDL) or LDL promotes formation of lipid-laden ‘‘foam’’ cells, a critical step in atherosclerotic lesion formation. CD36 facilitates ox-LDL uptake by binding the modified lipids and internalizing the particles [4]. CD36 was shown to delay degradation of native LDL in vivo[5]. These two functions would be predicted to have a pro-atherosclerotic effect
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