Deficiency of the mitochondrial glycerol 3‐phosphate dehydrogenase contributes to hepatic steatosis

Abstract

Mitochondrial glycerol 3‐phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a novel role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from NAFLD patients and mice (ob/ob, HFD and db/db). Liver‐specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet‐induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA‐seq revealed that mGPDH regulated endoplasmic reticulum (ER)‐related proteins and processes. mGPDH deletion exacerbated TM (ER stress inducer)‐induced hepatic steatosis, while TUDCA (ER stress inhibitor) rescued mGPDH depletion‐induced steatosis on a HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca²⁺ chelator BAPTA‐AM, mitochondrial permeability transition pore (mPTP) inhibitor CsA, or cyclophilin‐D (Cyp‐D) knockdown. mGPDH promoting Cyp‐D ubiquitination was also observed. Finally, liver‐specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion:mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp‐D ubiquitination, a key regulator of the mitochondrial Ca²⁺ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

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