The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis.
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.
['Ma|Di|D|', 'Liu|Tongyu|T|', 'Chang|Lin|L|', 'Rui|Crystal|C|', 'Xiao|Yuanyuan|Y|', 'Li|Siming|S|', 'Hogenesch|John B|JB|', 'Chen|Y Eugene|YE|', 'Lin|Jiandie D|JD|']
D000818:Animals D002784:Cholesterol D057906:Circadian Clocks D005786:Gene Expression Regulation D047908:Intracellular Signaling Peptides and Proteins D008077:Lipoproteins, LDL D008079:Lipoproteins, VLDL D008099:Liver D051379:Mice D008822:Mice, Transgenic D000071449:Proprotein Convertase 9 D043484:Proprotein Convertases D017346:Protein Serine-Threonine Kinases D011973:Receptors, LDL D012697:Serine Endopeptidases
liver cholesterol metabolism circadian clock gwas metabolism proprotein convertase subtilisin/kexin type 9 (PCSK9)