REV-ERBα Participates in Circadian SREBP Signaling and Bile Acid Homeostasis

• DOI: 10.1371/journal.pbio.1000181
• Publication Date: 2009-08-31T21:54:14Z
• Authors: Gwendal Le Martelot; Thierry Claudel; David Gatfield; Olivier Schaad; Benoît Kornmann; Giuseppe Lo Sasso; Antonio Moschetta; Ueli Schibler
• Keywords: 0301 basic medicine; info:eu-repo/classification/ddc/540; QH301-705.5; Blotting, Western; Golgi Apparatus; Mice, Transgenic; Endoplasmic Reticulum; Gas Chromatography-Mass Spectrometry; Bile Acids and Salts; Mice; 03 medical and health sciences; Biological Clocks; ddc:570; Animals; Cluster Analysis; Homeostasis; Biology (General); Cholesterol 7-alpha-Hydroxylase; Liver X Receptors; info:eu-repo/classification/ddc/570; Mice, Knockout; Gene Expression Profiling; Membrane Proteins; 16. Peace & justice; Circadian Rhythm; Cholesterol; Liver; ddc:540; Nuclear Receptor Subfamily 1, Group D, Member 1; Research Article

In mammals, many aspects of behavior and physiology, in particular cellular metabolism, are coordinated by the circadian timing system. Molecular clocks thought to rely on negative feedback loops clock gene expression that engender oscillations accumulation transcriptional regulatory proteins, such as orphan receptor REV-ERBα. Circadian transcription factors then drive daily rhythms clock-controlled output genes, for example genes encoding enzymes regulators metabolism. To gain insight into functions REV-ERBα, we carried out genome-wide transcriptome profiling experiments with liver RNA from wild-type mice, Rev-erbα knock-out or REV-ERBα overexpressing mice. On basis these genetic loss- gain-of-function experiments, concluded participates modulation sterol element-binding protein (SREBP) activity, thereby SREBP target involved cholesterol lipid This control is exerted via cyclic Insig2, a trans-membrane sequesters proteins endoplasmic reticulum membranes interferes proteolytic activation SREBPs Golgi membranes. also cholesterol-7α-hydroxylase (CYP7A1), rate-limiting enzyme converting bile acids. Our findings suggest this acts stimulation LXR nuclear receptors cyclically produced oxysterols. conclusion, our study suggests rhythmic acid metabolism not just driven alternating feeding–fasting cycles, but component clockwork circuitry.