title: Global and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis.
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-Bmal1-/-Apoe-/-) mice increases, whereas overexpression of BMAL1 in L-Bmal1-/-Apoe-/-and Apoe-/-mice 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-Bmal1-/-Apoe-/-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.
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.|Winthrop University Hospital, Mineola, New York, USA.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Pan
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.|Winthrop University Hospital, Mineola, New York, USA.|VA New York Harbor Healthcare System, Brooklyn, New York 11209, USA.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000150:complications* / Q000378:metabolism*; D001646:Bile; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications* / Q000378:metabolism*; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism
chemical_list: C462600:ABCG5 protein, mouse; D056930:ARNTL Transcription Factors; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D001057:Apolipoproteins E; C538961:Bmal1 protein, mouse; D050991:GATA4 Transcription Factor; D008074:Lipoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D002784:Cholesterol