Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Contributes to Hepatic Steatosis
Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Contributes to Hepatic Steatosis
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线粒体甘油 3-磷酸脱氢酶缺乏导致肝脂肪变性
DOI：
10.1002/hep.30507
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发表时间：
2019-07-01
期刊：
影响因子：
13.5
通讯作者：
Zheng, Hongting
中科院分区：
文献类型：
--
作者：
Zheng, Yi;Qu, Hua;Zheng, Hongting
线粒体甘油3-磷酸脱氢酶（mGPDH）是呼吸链的组成部分，最近的研究表明，它在肝脏葡萄糖稳态中起着重要作用。然而，其在肝脏脂质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。具体而言，来自NAFLD患者和小鼠的脂肪肝（ob/ob，高脂饮食[HFD]和db/db）中mGPDH表达和活性较低。小鼠肝脏特异性mGPDH耗竭或培养肝细胞中mGPDH敲低通过增强脂肪生成加剧了饮食诱导的甘油三酯蓄积和脂肪变性。RNA测序显示mGPDH调节内质网（ER）相关蛋白和过程。mGPDH缺失加重衣霉素（ER应激诱导剂）诱导的肝脂肪变性，而牛磺熊去氧胆酸（ER应激抑制剂）在HFD上挽救mGPDH缺失诱导的脂肪变性。此外，细胞内钙离子螯合剂1，2-双（2-氨基苯氧基）乙烷N，N，N '，N '-四乙酸乙酰氧基甲酯、线粒体通透性转换孔（mPTP）抑制剂环孢菌素A或亲环素D（Cyp-D）敲低均可消除mGPDH耗竭引起的内质网应激。还观察到mGPDH促进Cyp-D遍在化。最后，肝脏特异性mGPDH过表达减轻了ob/ob和HFD小鼠的肝脂肪变性。结论：mGPDH是肝脏脂质代谢的重要调节因子。它的缺乏通过抑制Cyp-D泛素化（线粒体Ca 2+传导通道mPTP的关键调节剂）诱导ER应激，并导致肝脂肪变性。mGPDH可能是治疗NAFLD的潜在靶点。
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 Ca2+ 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 Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.