Amelioration of late-onset hepatic steatosis in IDH2-deficient mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in the general population and can evolve into nonalcoholic steatohepatosis (NASH), cirrhosis, and complications such as liver failure and hepatocellular carcinoma. Recently, we reported that mitochondrial NADP⁺-dependent isocitrate dehydrogenase, encoded by the IDH2, plays an important role in the regulation of redox balance and oxidative stress levels, which are tightly associated with intermediary metabolism and energy production. In the present study, we showed that in mice targeted disruption of IDH2 attenuates age-associated hepatic steatosis by the activation of p38/cJun NH2-terminal kinase (JNK) and p53, presumably induced by the elevation of mitochondrial reactive oxygen species (ROS), which in turn resulted in the suppression of hepatic lipogenesis and inflammation via the upregulation of fibroblast growth factor 21 (FGF21) and the inhibition of NFκB signaling pathways. Our finding uncovers a new mechanism involved in hepatocellular steatosis and IDH2 may be a valuable therapeutic target for the management of NAFLD.

Keywords:

• IDH2
• hepatosteatosis
• mitochondrial ROS
• FGF21

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MSIP) [NRF-2016R1A2B1006280 and NRF-2015R1A4A1042271].

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MSIP) [NRF-2016R1A2B1006280 and NRF-2015R1A4A1042271].