摘要：SummaryCellular 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-specificSmodeletion. These studies demonstrate Smo in hepatocytes plays a regulatory role in sensing and feedback regulation of cholesterol balance driven by excess dietary cholesterol.Graphical abstractDisplay OmittedHighlights•Cholesterol and bile acid homeostasis is controlled by hepatocyte Smo activity•Smoloss blocked induction of LXRα, ABCG5, and AGCG8 that remove liver cholesterol•Smodeficiency increased hepatic CYP7A1 despite elevated SHP and bile acid levels•High-cholesterolSmo(−) livers were steatotic and did not induce ESRRA/PGC1α/PGC1βLipid; Molecular physiology; Molecular biology
