Abstract
Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. So far, the role of mouse Ces1/Ces1g deficiency in atherosclerosis is not elucidated. We generated Ces1/Ces1g−/− mice. Compared to wild-type mice, Ces1/Ces1g−/− mice had reduced plasma cholesterol levels. We then generated Ces1g−/−Ldlr−/− double knockout (DKO) mice, which were fed a Western diet for 16 weeks. Compared to Ldlr−/− mice, DKO mice displayed decreased plasma cholesterol and TG levels and reduced atherosclerotic lesions. Interestingly, knockdown of hepatic Ces1/Ces1g in Apoe−/− mice resulted in hyperlipidemia and exacerbated Western diet-induced atherogenesis. Mechanistically, global inactivation of Ces1/Ces1g inhibited intestinal cholesterol and fat absorption and Niemann-Pick C1 like 1 expression, and increased macrophage cholesterol efflux by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1. Ces1/Ces1g ablation also promoted M2 macrophage polarization and induced hepatic cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression. In conclusion, global loss of Ces1/Ces1g protects against the development of atherosclerosis by inhibiting intestinal cholesterol and triglyceride absorption and promoting macrophage cholesterol efflux.
Highlights
Cardiovascular diseases (CVDs) are the most prevalent cause of death globally, accounting for about 31% of all global deaths[1,2]
We have recently shown that hepatic Ces1/
LacZ staining of tissues isolated from Ces1+/− mice indicated that Ces[1] was expressed in a number of tissues, including brain, lung, liver, stomach, gallbladder, small intestine, colon, pancreas, spleen, kidney, white adipose tissue (WAT), adrenal and brown adipose tissue (BAT), but not in heart or skeletal muscle (Fig. 1E)
Summary
Cardiovascular diseases (CVDs) are the most prevalent cause of death globally, accounting for about 31% of all global deaths[1,2]. Over-expression of human CES1 in macrophages leads to an increase in cholesteryl ester hydrolysis and free cholesterol efflux and attenuation of atherosclerosis in Ldlr−/− mice[4]. Over-expression of human CES1 in the liver enhances reverse cholesterol transport and reduces atherosclerosis in Ldlr−/− mice[5,6]. These data suggest that human CES1 has cholesteryl ester hydrolase (CEH) activity. Global loss of Ces3/Ces1d is shown to reduce atherosclerosis in Ldlr−/− mice[13] It is unclear whether loss of mouse Ces1/Ces1g has any impact on atherosclerosis. Our data indicate that Ces1/Ces1g plays a critical role in the pathogenesis of atherosclerosis
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