Global and Hepatocyte-specific Ablation of Bmal1 Induces Hyperlipidaemia and Enhances Atherosclerosis

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Oct 11

PMID 27721414

Citations 57

Authors

Xiaoyue Pan

Christopher A Bradfield

M Mahmood Hussain

Affiliations

Soon will be listed here.

Abstract

Circadian rhythms controlled by clock genes affect plasma lipids. Here we show that global ablation of Bmal1 in Apoe and Ldlr mice and its liver-specific ablation in Apoe (L-Bmal1Apoe) mice increases, whereas overexpression of BMAL1 in L-Bmal1Apoe and Apoemice decreases hyperlipidaemia and atherosclerosis. Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Further, Bmal1 deficiency reduces expression of Shp and Gata4. Reductions in Shp increase Mtp expression and lipoprotein production, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and biliary cholesterol excretion. Forced SHP expression normalizes lipoprotein secretion with no effect on biliary cholesterol excretion, while forced GATA4 expression increases cholesterol excretion to the bile and reduces plasma lipids in L-Bmal1Apoe and Apoe mice. Thus, our data indicate that Bmal1 modulates lipoprotein production and biliary cholesterol excretion by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4.

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