Ces3/TGH Deficiency Improves Dyslipidemia and Reduces Atherosclerosis in Ldlr-/- Mice
Rationale: Carboxylesterase 3/triacylglycerol hydrolase (TGH) has been shown to participate in hepatic very-low density lipoprotein (VLDL) assembly. Deficiency of TGH in mice lowers plasma lipids and atherogenic lipoproteins without inducing hepatic steatosis.
Objective: Investigate the contribution of TGH to atherosclerotic lesion development in mice that lack low-density lipoprotein receptor (LDLR).
Methods and Results: Mice deficient in LDL receptor (Ldlr-/-) and mice lacking both TGH and LDLR (Tgh-/-/Ldlr-/-) were fed with Western-type diet for 12 weeks. Analysis of Tgh-/-/Ldlr-/- plasma showed an atheroprotective lipoprotein profile with decreased cholesterol in the VLDL and the LDL fractions, concomitant with elevated high density lipoprotein (HDL)-cholesterol. Significantly reduced plasma apolipoprotein B levels were also observed in Tgh-/-/Ldlr-/- mice. Consequently, Tgh-/-/Ldlr-/- mice presented with a significant reduction (54%, P＜0.01) of the high-fat, high-cholesterol diet induced atherosclerotic plaques when compared with Tgh+/+/Ldlr-/- mice in the cross-sectional aortic root analysis. TGH deficiency did not further increase liver steatosis despite lowering plasma lipids, mainly due to reduced hepatic lipogenesis. The ameliorated dyslipidemia in Tgh-/-/Ldlr-/- mice was accompanied with significantly improved insulin sensitivity.
Conclusions: Inhibition of TGH activity ameliorates atherosclerosis development and improves insulin sensitivity in Ldlr-/- mice.
- Cholesterol homeostasis
- Insulin resistance
- apolipoprotein B
- Received February 19, 2012.
- Accepted August 7, 2012.
- Copyright © 2012, American Heart Association