脂肪性肝炎
MFN2型
线粒体融合
线粒体
脂肪肝
生物
血红素加氧酶
线粒体DNA
品脱1
肝损伤
细胞生物学
内分泌学
内科学
粒体自噬
血红素
医学
生物化学
自噬
细胞凋亡
酶
疾病
基因
作者
Dongdong Li,Xiwei Yuan,Shiming Dong,Al-Dhamin Zaid,Jinghua Du,Na Fu,Yuemin Nan
摘要
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) and lacks effective treatment options. Heme oxygenase-1 (HO-1) is a critical defense against oxidative stress and inflammation in the liver injury. This study aims to investigate the protective role and underlying mechanisms of HO-1 in NASH pathogenesis.The hepatocyte-specific HO-1 knockout (HO-1HEPKO ) mice on a C57BL/6J background (HO-1fl/fl /Alb-Cre) were generated and fed a high-fat/western-style diet (HFD) or methionine-choline-deficient diet (MCD). Changes in mitochondrial ultrastructure were observed by transmission electron microscopy and confocal microscopy. A mitochondrial PCR array was used to identify the crucial genes associated with mitochondrial dysfunction.Hepatocyte-specific HO-1HEPKO mice developed steatohepatitis with severe steatosis, ballooning, and necroinflammation. Dysregulated hepatic expression of mitochondria-related proteins, including DRP1, Tomm20, MFN1 and MFN2 were detected in NASH animals. Ultrastructural mitochondrial damage was observed in HO-1HEPKO mice. Mitochondrial dysfunction was recapitulated in HO-1-knockdown cells in vitro, as evidenced by decreased membrane potential, reduced ATP content, and mtDNA damage. Conversely, HO-1 overexpression restored these changes in vitro. Mechanistically, HO-1 deficiency reduced the inhibitory effect on Tomm20, leading to mitochondrial dysfunction, and thereby causing steatohepatitis.HO-1 attenuates diet-induced steatohepatitis by preventing mitochondrial dysfunction, indicating that HO-1 may constitute a potential therapeutic target for NASH.
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