Affiliation:
1. Department of Traditional and Western Medical Hepatology Third Hospital of Hebei Medical University Shijiazhuang China
2. Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases Shijiazhuang China
Abstract
AbstractAimNonalcoholic 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.MethodsThe 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.ResultsHepatocyte‐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.ConclusionsHO‐1 attenuates diet‐induced steatohepatitis by preventing mitochondrial dysfunction, indicating that HO‐1 may constitute a potential therapeutic target for NASH.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Anhui Province
Natural Science Foundation of Hebei Province
Hebei Provincial Key Research Projects
Cited by
4 articles.
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