LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis

Abstract

the pathophysiology of atherosclerosis ( 2 ). After LDL particles enter the intima of the artery wall, they can interact with proteoglycans, which are structural proteins residing in the extracellular matrix that consist of one or more glycosaminoglycan (GAG) side-chains attached to core proteins. The LDL-proteoglycan complex is generally regarded as an electrostatic interaction ( 3 ). The sulfation pattern of the acidic sugar groups that form the GAG chains on the proteoglycans results in an overall negative charge that can interact with clusters of positively charged amino acid residues on apoB-100, the primary apolipoprotein present on the LDL particle ( 4 ). A proteoglycan frequently deposited in atherosclerotic plaques of humans ( 5, 6 ) and mice is biglycan (BGN) ( 7 ).While plasma LDL cholesterol concentrations are predictive of the extent of atherosclerosis, LDL particles are heterogeneous in size and composition, and this heterogeneity may provide additional useful information about the role of LDL in atherosclerosis. For instance, studies have shown that diet-induced alterations in the FA composition of LDL core cholesteryl esters (CEs) can infl uence the atherogenic potential of LDL particles ( 8-11 ). In nonhuman primates, consumption of dietary MUFAs resulted in LDL particles containing a CE core enriched in cholesterol oleate (CO), which were positively associated with coronary artery atherosclerosis ( r = 0.8) ( 10, 11 ). Importantly, a similar diet-related shift in the CE FA composition of LDL has been observed in humans in which consumption of oleate-enriched diets resulted in elevations in the percentage of CO in the LDL CE ( 12 ). Additionally, the large Atherosclerosis Risk in Communities Study revealed a Abstract Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O -acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affi nity of the LDL particle for arterial proteoglycans. ApoB-100-only Ldlr − /− mice with and without Soat2 gene deletions were fed diets enriched in either cis -MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affi nity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO

Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association

“…5,6,[46][47][48][49][50][51] The results strongly support the strong atherogenicity of saturated fatty acids through effects to raise LDL cholesterol concentrations compared with the effects of n-6 polyunsaturated fatty acids. Although monounsaturated fatty acids promoted atherosclerosis despite lowering LDL cholesterol, mechanisms related to LDL binding to proteoglycan may differ in humans.…”

“…49 Atherosclerosis extent has consistently been positively correlated with high LDL proteoglycan binding affinity. 48,50 Finally, a diet typical of the 1980s in the United States, high in saturated fat, fed to rhesus monkeys for 2 years increased serum cholesterol to 383 mg/dL and caused atherosclerosis that had complex pathological features similar to atherosclerosis in young human adults who died of trauma. 51 In contrast, a "prudent" diet recommended by the AHA to prevent CHD, low in saturated and high in polyunsaturated fat, produced lower serum cholesterol levels, 199 mg/dL, and less atherosclerosis.…”

Cholesterol Esters (CE) Derived From Hepatic Sterol O-Acyltransferase 2 (SOAT2) Are Associated With More Atherosclerosis Than CE From Intestinal SOAT2

“…Excessive circulating apoB-containing lipoproteins, especially LDL, would be retained in the arterial intima 6 and may initiate atherogenesis. SOAT2 knockout animals have delayed atherosclerosis development that is presumably due to the loss of capability of esterification of cholesterol oleate and packaging of those cholesterol esters into potentially atherogenic lipoprotein particles.…”

“…SOAT subtype1 (SOAT1) is expressed in a variety of tissues while SOAT subtype2 (SOAT2) is expressed preferentially in enterocytes of the intestine and hepatocytes of the liver 2 , where one of its roles is to generate CE for packaging into chylomicrons and very low-density lipoproteins (VLDL), respectively 3, 4 . Cholesterol esters, especially cholesterol oleate, are major components of atherogenic lipoproteins, appearing to play a critical role in the pathogenesis of atherosclerosis 5, 6 .…”

Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

“…A recent study showed that SOAT2 KO versus WT mice or mice fed FO versus monounsaturated fat had plasma LDL enriched in PUFA CE species and bound with less affi nity to proteoglycans, suggesting a mechanism by which apoB lipoproteins from mice fed dietary PUFA may be less atherogenic ( 51 ). Although PUFA lipid species are more easily oxidized than their saturated and monounsaturated counterparts ( 52,53 ) and ox-CE species have been identifi ed in human tissue samples from endarterectomies ( 28 ), no arterial ox-CEs were detected in our study, despite signifi cant enrichment of circulating and tissue lipids with by guest, on www.jlr.org Downloaded from large decrease in hepatic TG content does not necessarily result in decreased TG secretion.…”