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肝脏再生增强因子:线粒体功能与脂肪性肝炎

Augmenter of liver regeneration: Mitochondrial function and steatohepatitis.

作者信息

Verma Alok Kumar, Sharma Akanksha, Subramaniyam Nithyananthan, Gandhi Chandrashekhar R

机构信息

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Cincinnati VA Medical Center, Cincinnati, Ohio, USA.

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

出版信息

J Hepatol. 2022 Nov;77(5):1410-1421. doi: 10.1016/j.jhep.2022.06.019. Epub 2022 Jun 28.

Abstract

Augmenter of liver regeneration (ALR), a ubiquitous fundamental life protein, is expressed more abundantly in the liver than other organs. Expression of ALR is highest in hepatocytes, which also constitutively secrete it. ALR gene transcription is regulated by NRF2, FOXA2, SP1, HNF4α, EGR-1 and AP1/AP4. ALR's FAD-linked sulfhydryl oxidase activity is essential for protein folding in the mitochondrial intermembrane space. ALR's functions also include cytochrome c reductase and protein Fe/S maturation activities. ALR depletion from hepatocytes leads to increased oxidative stress, impaired ATP synthesis and apoptosis/necrosis. Loss of ALR's functions due to homozygous mutation causes severe mitochondrial defects and congenital progressive multiorgan failure, suggesting that individuals with one functional ALR allele might be susceptible to disorders involving compromised mitochondrial function. Genetic ablation of ALR from hepatocytes induces structural and functional mitochondrial abnormalities, dysregulation of lipid homeostasis and development of steatohepatitis. High-fat diet-fed ALR-deficient mice develop non-alcoholic steatohepatitis (NASH) and fibrosis, while hepatic and serum levels of ALR are lower than normal in human NASH and NASH-cirrhosis. Thus, ALR deficiency may be a critical predisposing factor in the pathogenesis and progression of NASH.

摘要

肝再生增强因子(ALR)是一种普遍存在的基础生命蛋白,在肝脏中的表达量高于其他器官。ALR在肝细胞中的表达最高,肝细胞也组成性地分泌该蛋白。ALR基因转录受NRF2、FOXA2、SP1、HNF4α、EGR - 1和AP1/AP4调控。ALR的FAD连接的巯基氧化酶活性对于线粒体内膜间隙中的蛋白质折叠至关重要。ALR的功能还包括细胞色素c还原酶和蛋白质铁硫簇成熟活性。肝细胞中ALR的缺失会导致氧化应激增加、ATP合成受损以及细胞凋亡/坏死。由于纯合突变导致ALR功能丧失会引起严重的线粒体缺陷和先天性进行性多器官衰竭,这表明具有一个功能性ALR等位基因的个体可能易患涉及线粒体功能受损的疾病。肝细胞中ALR的基因缺失会诱导线粒体结构和功能异常、脂质稳态失调以及脂肪性肝炎的发展。高脂饮食喂养的ALR缺陷小鼠会发展为非酒精性脂肪性肝炎(NASH)和肝纤维化,而在人类NASH和NASH肝硬化中,肝脏和血清中的ALR水平低于正常水平。因此,ALR缺乏可能是NASH发病机制和进展中的一个关键易感因素。

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