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Cell Rep. 2015 Nov 24;13(8):1658-69. doi: 10.1016/j.celrep.2015.10.033. Epub 2015 Nov 12.

A Diet-Sensitive BAF60a-Mediated Pathway Links Hepatic Bile Acid Metabolism to Cholesterol Absorption and Atherosclerosis.

Author information

1
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: zxmeng@umich.edu.
2
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Center for Advanced Models for Translational Sciences and Therapeutics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
4
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
5
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: jdlin@umich.edu.

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.

PMID:
26586440
PMCID:
PMC4662911
DOI:
10.1016/j.celrep.2015.10.033
[Indexed for MEDLINE]
Free PMC Article

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