Ces3/TGH deficiency improves dyslipidemia and reduces atherosclerosis in Ldlr(-/-) mice.

Abstract

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.

• Authors: Jihong Lian, Ariel D Quiroga, Lena Li, Richard Lehner
• Journal: Circulation research (Circ Res) Vol. 111 Issue 8 Pg. 982-90 (Sep 28 2012) ISSN: 1524-4571 [Electronic] United States
• PMID: 22872154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins B
• Blood Glucose
• Cholesterol, HDL
• Cholesterol, LDL
• Cholesterol, VLDL
• Fatty Acids
• Insulin
• Receptors, LDL
• Lipase

Topics

• Animals
• Aorta (metabolism, pathology)
• Apolipoproteins B (blood)
• Blood Glucose (metabolism)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Cholesterol, VLDL (blood)
• Coronary Artery Disease (genetics, metabolism, pathology)
• Disease Models, Animal
• Dyslipidemias (genetics, metabolism)
• Fatty Acids (metabolism)
• Fatty Liver (genetics, metabolism, pathology)
• Female
• Insulin (blood)
• Insulin Resistance (physiology)
• Lipase (deficiency, genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Receptors, LDL (genetics, metabolism)