title: The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis.
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.
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and.
authors.forename: Di
authors.initials: D
authors.lastname: Ma
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109 and.
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and.
authors.forename: Crystal
authors.initials: C
authors.lastname: Rui
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and.
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109 and.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: From the Life Sciences Institute and Department of Cell and Developmental Biology and jdlin@umich.edu.
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; C523598:Trib1 protein, mouse; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: cholesterol metabolism; circadian clock; gwas; liver; metabolism; proprotein convertase subtilisin/kexin type 9 (PCSK9)