Hepatocyte activity of the cholesterol sensor smoothened regulates cholesterol and bile acid homeostasis in mice

• Published in: iScience Vol. 24; no. 9; p. 103089
• Main Authors: Dalton, George D., Oh, Seh-Hoon, Tang, Linda, Zhang, Stephanie, Brown, Amanda L., Varadharajan, Venkateshwari, Baleanu-Gogonea, Camelia, Gogonea, Valentin, Pathak, Preeti, Brown, J. Mark, Diehl, Anna Mae
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-09-2021; Elsevier
• Subjects: Lipid; Molecular biology; Molecular physiology; Molecular biology; Molecular physiology; Lipid
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103089

Cellular cholesterol is regulated by at least two transcriptional mechanisms involving sterol-regulatory-element-binding proteins (SREBPs) and liver X receptors (LXRs). Although SREBP and LXR pathways are the predominant mechanisms that sense cholesterol in the endoplasmic reticulum and nucleus to alter sterol-regulated gene expression, evidence suggests cholesterol in plasma membrane can be sensed by proteins in the Hedgehog (Hh) pathway which regulate organ self-renewal and are a morphogenic driver during embryonic development. Cholesterol interacts with the G-protein-coupled receptor Smoothened (Smo), which impacts downstream Hh signaling. Although evidence suggests cholesterol influences Hh signaling, it is not known whether Smo-dependent sterol sensing impacts cholesterol homeostasis in vivo. We examined dietary-cholesterol-induced reorganization of whole-body sterol and bile acid (BA) homeostasis in adult mice with inducible hepatocyte-specific Smo deletion. These studies demonstrate Smo in hepatocytes plays a regulatory role in sensing and feedback regulation of cholesterol balance driven by excess dietary cholesterol.
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•Cholesterol and bile acid homeostasis is controlled by hepatocyte Smo activity•Smo loss blocked induction of LXRα, ABCG5, and AGCG8 that remove liver cholesterol•Smo deficiency increased hepatic CYP7A1 despite elevated SHP and bile acid levels•High-cholesterol Smo (−) livers were steatotic and did not induce ESRRA/PGC1α/PGC1β
Lipid; Molecular physiology; Molecular biology