The mechanism and role of intracellular ?-ketoglutarate reduction in hepatic stellate cell activation.

ABSTRACT: BACKGROUND:The activation of hepatic stellate cells (HSCs) plays a central role in liver fibrosis. ?-ketoglutarate is a natural metabolite and previous studies have shown that increase in intracellular ?-ketoglutarate can inhibit HSC activation. AIM:The aim of the present study is to determine the changes and role of intracellular ?-ketoglutarate in HSC activation and clarify its mechanism of action. METHODS:A human HSC cell line (LX-2) and the primary mouse HSC were used in the present study. We detected the changes of intracellular ?-ketoglutarate levels and the expression of enzymes involved in the metabolic processes during HSC activation. We used siRNA to determine the role of intracellular ?-ketoglutarate in HSC activation and elucidate the mechanism of the metabolic changes. RESULTS:Our results demonstrated that intracellular ?-ketoglutarate levels decreased with an HSC cell line and primary mouse HSC activation, as well as the expression of isocitrate dehydrogenase 2 (IDH2), an enzyme that catalyzes the production of ?-ketoglutarate. In addition, knockdown of IDH2 efficiently promoted the activation of HSCs, which was able to be reversed by introduction of an ?-ketoglutarate analogue. Furthermore, we demonstrated that ?-ketoglutarate regulated HSC activation is independent of transforming growth factor-?1 (TGF-?1). CONCLUSIONS:Our findings demonstrated that decrease in IDH2 expression limits the production of ?-ketoglutarate during HSC activation and in turn promotes the activation of HSCs through a TGF-?1 independent pathway. The present study suggests that IDH2 and ?-ketoglutarate may be potential new targets for the prevention and treatment of liver fibrosis.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC7069903 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature