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

Abstract

SummaryRecent 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.

Highlights

The liver is unique in its ability to regenerate in response to injury
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 PPARa and FXR are potential therapeutic targets for modulating liver regeneration
PPARa activation induces the transcription of Sox9 and FXR activation suppresses the transcription of Sox9 in vitro PPARa, FXR and Sox9 were expressed in HepG2 cells (Ghonem et al, 2014; Ramos Pittol et al, 2020)

Summary

Introduction

The liver is unique in its ability to regenerate in response to injury. Recent studies have revealed that during liver injury, new hepatocytes arise by replication of hybrid hepatocytes (HybHP). The HybHPs expressed both hepatocyte nuclear factor 4 alpha (Hnf4a) and low levels of Sox which was expressed in adjacent biliary ductules. These HybHPs undergo extensive proliferation to replenish the liver mass after chronic hepatocyte-depleting injury (Font-Burgada et al, 2015). The heterogeneity and demarcated metabolic zones of the liver enable hepatocytes flexible adaption to different circumstances (Wu et al, 2020). PP hepatocytes are responsible for gluconeogenesis and fatty acid b-oxidation (FAO), in contrast, pericentral hepatocytes are more involved in glycolysis and lipogenesis (Hijmans et al, 2014)

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