Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice

Abstract

Deficiency of acyl CoA:cholesterol acyltransferase 2 (ACAT2) in mice results in a reduction in cholesterol ester synthesis in the small intestine and liver, which in turn limits intestinal cholesterol absorption, hepatic cholesterol gallstone formation, and the accumulation of cholesterol esters in the plasma lipoproteins. Here we examined the contribution of ACAT2-derived cholesterol esters to atherosclerosis by crossing ACAT2-deficient (ACAT2 -/-) mice with apolipoprotein (apo) E-deficient (ApoE -/-) mice, an atherosclerosissusceptible strain that has impaired apoE-mediated clearance of apoB-containing lipoproteins. ACAT2 -/-ApoE -/-mice and ACAT2 ؉/؉ ApoE -/-(control) mice had similar elevations of plasma apoB and total plasma lipids; however, the lipid cores of the apoB-containing lipoproteins in ACAT2 -/-ApoE -/-mice contained primarily triglycerides rather than cholesterol esters. At 30 wk of age, only the control mice had significant atherosclerosis, which was nearly absent in ACAT2 -/-ApoE -/-mice. ACAT2 deficiency in the apoE-deficient background also led to a compensatory increase in the activity of lecithin͞cholesterol acyltransferase, the major plasma cholesterol esterification enzyme, which increased highdensity lipoprotein cholesterol esters. Our results demonstrate the crucial role of ACAT2-derived cholesterol esters in the development of atherosclerosis in mice and suggest that triglyceride-rich apoBcontaining lipoproteins are not as atherogenic as those containing cholesterol esters. Our results also support the rationale of pharmacological inhibition of ACAT2 as a therapy for atherosclerosis.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

“…We identified other genes related to lipid metabolism whose expression is up-regulated in the liver of NFR-treated mice, including Soat2 (also abbreviated as Acat2), which was also found among the top genes up-regulated in MEFs in an eIF2α phosphorylation-dependent manner. This enzyme contributes to cholesterol ester synthesis in the small intestine and liver and therefore can promote hypercholesterolaemia and atherosclerosis (59), two metabolic disturbances often observed in HIV-PI-treated patients. All together these data further show that the ISR is a key metabolic regulator that can affect multiple pathways related to lipid metabolism.…”

Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss

“…On the other hand ACAT2 is expressed exclusively in lipoprotein-producingcells such as intestinal enterocytes and hepatocytes in the liver (7,8), and plays a gatekeeper role in the production of atherogenic apoB-containing lipoproteins (6 -10). In support of this concept, when compared with wild type controls, ACAT2-deficient mice have reduced cholesterol absorption (11)(12)(13)(14), are depleted in hepatic cholesteryl esters (CE) (7)(8)(9)(10)(11)(12)(13)(14), and are protected against diet-induced gallstone formation and atherosclerosis (10,11,15). Importantly, the hepatic storage and secretion of CE into apoB-containing lipoproteins is virtually absent in mice lacking ACAT2 (9 -14), indicating that ACAT2 is the sole cholesterol-esterifying enzyme in mouse liver.…”

Molecular Mechanism for Changes in Proteoglycan Binding on Compositional Changes of the Core and the Surface of Low-Density Lipoprotein–Containing Human Apolipoprotein B100

“…13 Willner et al recently showed that the enrichment of cholesterol of LDL is another important risk factor for atherosclerosis; triglyceride-rich apoB-containing lipoproteins are not as atherogenic as those containing cholesteryl esters. 14 The authors proposed that the inflammatory response in atherosclerosis occurs primarily in response to toxicity from cholesterol accumulation in lesions. 14 However, it has also been shown that the triglyceride content of LDL are reciprocally related to the number of exposed free lysine amino groups of apoB100.…”