Heme oxygenase-1 prevents non-alcoholic steatohepatitis through modulating mitochondrial quality control

Dongdong Li; Xiwei Yuan; Shiming Dong; Zaid Al-Dhamin; Jinghua Du; Na Fu; Yuemin Nan

doi:10.1111/apha.13918

Heme oxygenase-1 prevents non-alcoholic steatohepatitis through modulating mitochondrial quality control

Acta Physiol (Oxf). 2023 Mar;237(3):e13918. doi: 10.1111/apha.13918. Epub 2023 Jan 18.

Authors

Dongdong Li^{1

2}, Xiwei Yuan^{1

2}, Shiming Dong^{1

2}, Zaid Al-Dhamin^{1

2}, Jinghua Du^{1

2}, Na Fu^{1

2}, Yuemin Nan^{1

2}

Affiliations

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.

PMID: 36602456
DOI: 10.1111/apha.13918

Abstract

Aim: 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.

Methods: The hepatocyte-specific HO-1 knockout (HO-1^HEPKO ) mice on a C57BL/6J background (HO-1^fl/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.

Results: Hepatocyte-specific HO-1^HEPKO 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-1^HEPKO 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.

Conclusions: HO-1 attenuates diet-induced steatohepatitis by preventing mitochondrial dysfunction, indicating that HO-1 may constitute a potential therapeutic target for NASH.

Keywords: heme oxygenase-1; mitochondrial function; nonalcoholic steatohepatitis; oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Heme Oxygenase-1* / genetics
Heme Oxygenase-1* / metabolism
Liver / metabolism
Mice
Mice, Inbred C57BL
Mitochondria* / metabolism
Non-alcoholic Fatty Liver Disease* / genetics
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology

Substances

Heme Oxygenase-1