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J Biol Chem. 2015 Dec 25;290(52):31003-12. doi: 10.1074/jbc.M115.685982. Epub 2015 Nov 7.

The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis.

Author information

1
From the Life Sciences Institute and Department of Cell and Developmental Biology and.
2
Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109 and.
3
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
4
From the Life Sciences Institute and Department of Cell and Developmental Biology and jdlin@umich.edu.

Abstract

Disruption of the body clock has been recognized as a risk factor for cardiovascular disease. How the circadian pacemaker interacts with the genetic factors associated with plasma lipid traits remains poorly understood. Recent genome-wide association studies have identified an expanding list of genetic variants that influence plasma cholesterol and triglyceride levels. Here we analyzed circadian regulation of lipid-associated candidate genes in the liver and identified two distinct groups exhibiting rhythmic and non-rhythmic patterns of expression during light-dark cycles. Liver-specific inactivation of Bmal1 led to elevated plasma LDL/VLDL cholesterol levels as a consequence of the disruption of the PCSK9/LDL receptor regulatory axis. Ablation of the liver clock perturbed diurnal regulation of lipid-associated genes in the liver and markedly reduced the expression of the non-rhythmically expressed gene Trib1. Adenovirus-mediated rescue of Trib1 expression lowered plasma PCSK9 levels, increased LDL receptor protein expression, and restored plasma cholesterol homeostasis in mice lacking a functional liver clock. These results illustrate an unexpected mechanism through which the biological clock regulates cholesterol homeostasis through its regulation of non-rhythmic genes in the liver.

KEYWORDS:

cholesterol metabolism; circadian clock; gwas; liver; metabolism; proprotein convertase subtilisin/kexin type 9 (PCSK9)

PMID:
26547624
PMCID:
PMC4692226
DOI:
10.1074/jbc.M115.685982
[Indexed for MEDLINE]
Free PMC Article

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