Background: NAFLD is the most common liver disorder worldwide. Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a component of respiratory chain, and reported to involve in hepatic glucose homeostasis, however its function in hepatic lipid metabolism is unclear. We previously observed a low mGPDH expression in fatty liver. Thus, this study is to determine the role of mGPDH in liver lipid metabolism and steatosis.
Methods: mGPDH-/- mice were fed chow or HFD. ob/ob and HFD mice were treated adenovirus-associated virus (AAV) 8-mGPDH. Hepatic and plasma lipid profile were assessed. Livers were analyzed by histology, qRT-PCR and immunoblot. RNA-sequencing was performed using hepatocyte LO2 infected mGPDH under FFA.
Results: In fatty livers of NAFLD patients and mice (ob/ob, HFD and db/db), mGPDH expression is inhibited. Livers of mGPDH-/- mice become sensitivity to HFD and potentiate to steatosis. Mechanistically, RNA-sequencing reveals mGPDH regulates endoplasmic reticulum (ER)-related proteins, and we further confirm its effect on depressing hepatic lipogenesis is mainly through inhibiting ER stress by activation of the IRE1α branch of the UPR. Moreover, rescuing hepatic mGPDH deficient in ob/ob and HFD mice by liver target AAV8 may be a mechanism for ameliorating hepatic steatosis.
Conclusions: mGPDH serves as a novel suppressor for hepatic lipogenesis, and direct targeting of mGPDH may have therapeutic potential for NAFLD.
Y. Zheng: None. H. Zheng: None.