Department of Endocrinology, Translational Research Key Laboratory for Diabetes, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
Hepatology. 2019 Jul;70(1):84-97. doi: 10.1002/hep.30507. Epub 2019 Mar 15.
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 role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high-fat diet [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-sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)-related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)-induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion-induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca chelator 1,2-bis (2-aminophenoxy) ethane N,N,N´,N´-tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, 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 Ca conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.
线粒体甘油-3-磷酸脱氢酶（mGPDH）是呼吸链的一个组成部分，最近的研究表明它在肝葡萄糖稳态中发挥着重要作用。然而，其在肝脂代谢中的功能尚不清楚。在这里，我们确定了 mGPDH 在非酒精性脂肪性肝病（NAFLD）中的作用。具体来说，mGPDH 的表达和活性在患有 NAFLD 的患者和小鼠（ob/ob、高脂肪饮食[HFD]和 db/db）的脂肪肝中较低。在小鼠中特异性敲除 mGPDH 或在培养的肝细胞中敲低 mGPDH 会通过增强脂肪生成加剧饮食诱导的甘油三酯积累和脂肪变性。RNA 测序显示 mGPDH 调节内质网（ER）相关蛋白和过程。mGPDH 缺失加剧了他莫昔芬（ER 应激诱导剂）诱导的肝脂肪变性，而牛磺熊脱氧胆酸（ER 应激抑制剂）挽救了 HFD 诱导的 mGPDH 缺失引起的脂肪变性。此外，mGPDH 缺失引起的 ER 应激可以被细胞内 Ca 螯合剂 1,2-双（2-氨基苯氧基）乙烷 N,N,N´,N´-四乙酸乙二胺四乙酸酯、线粒体通透性转换孔（mPTP）抑制剂环孢菌素 A 或亲环蛋白-D（Cyp-D）敲低所阻断。还观察到 mGPDH 促进 Cyp-D 泛素化。最后，肝特异性 mGPDH 过表达减轻了 ob/ob 和 HFD 小鼠的肝脂肪变性。结论：mGPDH 是肝脂代谢的关键调节因子。其缺乏通过抑制 Cyp-D 泛素化来诱导 ER 应激，Cyp-D 是线粒体 Ca 电导通道 mPTP 的关键调节因子，导致肝脂肪变性。mGPDH 可能是治疗 NAFLD 的潜在治疗靶点。
