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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.

Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr −/− mice