Hepatocyte SREBP Signaling Mediates Clock Communication Within the Liver

Authors

Dongyin Guan
Hosung Bae
Dishu Zhou
Ying Chen
Chunjie Jiang
Cam Mong La
Yang Xiao
Kun Zhu
Wenxiang Hu
Trang Minh Trinh
Panpan Liu
Ying Xiong
Bishuang Cai
Cholsoon Jang
Mitchell A Lazar

Publication Date

4-17-2023

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI163018

PMID

37066875

PMCID

PMC10104893

PubMedCentral® Posted Date

4-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Sterol Regulatory Element Binding Protein 1, Nuclear Receptor Subfamily 1, Group D, Member 1, Liver, Hepatocytes, Circadian Rhythm, Communication, Epigenetics, Homeostasis, Hepatology, Metabolism

Abstract

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.

Comments

Associated Data