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

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

Powering the powerhouse: Heme oxygenase‐1 regulates mitochondrial function in non‐alcoholic fatty liver disease (NAFLD)

“…[2][3][4] However, in 2014, Jais et al created hepatocyte-specific HO-1 knockout mice they named Lhoko and showed the opposite, that is, HO-1 seemed to exert deleterious effects and promote inflammation in NAFLD. 5 This work demonstrated increased HO-1 mRNA expression in diet-induced fatty liver, similar to the present Li et al study, 1 which found that HO-1 mRNA levels were also significantly higher with high-fat feeding-induced NAFLD. However, the two studies have entirely different findings regarding the role of HO-1 in NAFLD.…”

“…5 Jais et al crossed these animals with Alb-Cre transgenic mice generating the Lhoko mice, 5 which caused a frameshift in exon 3 and an early stop codon that resulted in a truncated peptide consisting of nine amino acids. One must wonder whether the truncated nine amino acid peptide originating from the HO-1 gene in the Lhoko mice might have some protective action causing a differential finding compared to the HO-1 HEPKO mice described by Li et al 1 The vast majority of the scientific literature has demonstrated the protective effects of HO-1 as a protector against oxidative stress and as an inhibitor of lipid accumulation with favorable effects on health and NAFLD (Figure 1).…”

“…In this issue, Li et al 1 advanced our understanding of heme oxygenase-1 (HO-1) in non-alcoholic fatty liver disease (NAFLD). They developed hepatocyte-specific HO-1 knockout (KO) mice (HO-1 HEPKO ) and used LO-2 human hepatocytes with HO-1 knocked down or overexpressed.…”

“…The dichotomy in the findings could arise from how the mice were generated in each study. Li et al utilized CRISPR technology to generate the HO-1 HEPKO mice, 1 and Jais et al used classical homologous recombination to insert LoxP sites flanking exon 2 of the HO-1 gene locus. 5 Jais et al crossed these animals with Alb-Cre transgenic mice generating the Lhoko mice, 5 which caused a frameshift in exon 3 and an early stop codon that resulted in a truncated peptide consisting of nine amino acids.…”

“…In the study by Li et al 1 they determined the effects of HO-1 on mitochondria with and without treatments with palmitic acid to mimic the environment for determining the mechanism by which HO-1 interacts with mitochondrial function in fat-loaded hepatocytes. HO-1 has been previously shown to be located in the mitochondria of the liver and controls mitochondrial heme and its metabolism to bilirubin.…”