Hepatocyte SREBP signaling mediates clock communication within the liver

J Clin Invest. 2023 Apr 17;133(8):e163018. doi: 10.1172/JCI163018.


Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erbα and -β (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage-activating protein (SCAP) was required for Reverb-hDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB-depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBα and β (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO.

Keywords: Epigenetics; Hepatology; Homeostasis; Metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Circadian Rhythm / physiology
  • Communication
  • Hepatocytes / metabolism
  • Liver* / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1* / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1* / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism


  • Sterol Regulatory Element Binding Protein 1
  • Nuclear Receptor Subfamily 1, Group D, Member 1