title: A Diet-Sensitive BAF60a-Mediated Pathway Links Hepatic Bile Acid Metabolism to Cholesterol Absorption and Atherosclerosis.
abstract: Dietary nutrients interact with gene networks to orchestrate adaptive responses during metabolic stress. Here, we identify Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the mouse liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. Baf60a expression was elevated in the liver following feeding with a western diet. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. Baf60a stimulates expression of genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on target genes. These studies elucidate a regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet consumption.
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: zxmeng@umich.edu.
authors.forename: Zhuo-Xian
authors.initials: ZX
authors.lastname: Meng
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Jiangyin
authors.initials: J
authors.lastname: Bao
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yaqiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: jdlin@umich.edu.
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004032:Diet / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001647:Bile Acids and Salts; D002868:Chromosomal Proteins, Non-Histone; C529549:Smarcd1 protein, mouse; D002784:Cholesterol