Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate

Shenghui Liu; Dan Qin; Yi Yan; Jiayan Wu; Lihua Meng; Wendong Huang; Liqiang Wang; Xiangmei Chen; Lisheng Zhang

doi:10.1016/j.isci.2021.103003

Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9⁺ hepatocyte fate

iScience. 2021 Aug 19;24(9):103003. doi: 10.1016/j.isci.2021.103003. eCollection 2021 Sep 24.

Authors

Shenghui Liu¹, Dan Qin¹, Yi Yan¹, Jiayan Wu¹, Lihua Meng¹, Wendong Huang², Liqiang Wang³, Xiangmei Chen³, Lisheng Zhang¹

Affiliations

¹ College of Veterinary Medicine/Bio-medical Center, Huazhong Agricultural University, Wuhan, Hu Bei 430070, China.
² Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
³ Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing 100853, China.

Abstract

Recent research has indicated the adult liver Sox9⁺ cells located in the portal triads contribute to the physiological maintenance of liver mass and injury repair. However, the physiology and pathology regulation mechanisms of adult liver Sox9⁺ cells remain unknown. Here, PPARα and FXR bound to the shared site in Sox9 promoter with opposite transcriptional outputs. PPARα activation enhanced the fatty acid β-oxidation, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production, thus promoting proliferation and differentiation of Sox9⁺ hepatocytes along periportal (PP)-perivenous (PV) axis. However, FXR activation increased glycolysis but decreased OXPHOS and ATP production, therefore preventing proliferation of Sox9⁺ hepatocytes along PP-PV axis by promoting Sox9⁺ hepatocyte self-renewal. Our research indicates that metabolic nuclear receptors play critical roles in liver progenitor Sox9⁺ hepatocyte homeostasis to initiate or terminate liver injury-induced cell proliferation and differentiation, suggesting that PPARα and FXR are potential therapeutic targets for modulating liver regeneration.

Keywords: Cell biology; Cellular physiology; Human metabolism; Molecular physiology.