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

• Hepatic Baf60a is a diet-sensitive regulator of cholesterol homeostasis
• Hepatic Baf60a deficiency impairs bile acid metabolism and cholesterol absorption
• Baf60a/CAR form a feedforward regulatory loop to regulate bile acid metabolism genes
• Liver-specific Baf60a inactivation protects mice from diet-induced atherosclerosis

SummaryDietary 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.

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