Global Inactivation of Carboxylesterase 1 (Ces1/Ces1g) Protects Against Atherosclerosis in Ldlr -/- Mice

Sci Rep. 2017 Dec 19;7(1):17845. doi: 10.1038/s41598-017-18232-x.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Atherosclerosis / blood
  • Atherosclerosis / metabolism*
  • Carboxylic Ester Hydrolases / metabolism*
  • Cholesterol / blood
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Hyperlipidemias / blood
  • Hyperlipidemias / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / pathology
  • Liver / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Triglycerides / blood

Substances

  • ATP Binding Cassette Transporter 1
  • Triglycerides
  • Cholesterol
  • Carboxylic Ester Hydrolases
  • carboxylesterase 1, mouse