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Ces3/TGH deficiency improves dyslipidemia and reduces atherosclerosis in Ldlr(-/-) mice
Jihong Lian1, Ariel D Quiroga, Lena Li
1Department of Pediatrics, Group on Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
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:
To 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 a 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 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 dieteninduced 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.
