Heme oxygenase 1 alleviates nonalcoholic steatohepatitis by suppressing hepatic ferroptosis

Abstract

Background Heme oxygenase 1 (HO-1) has an influential but insufficiently investigated effect on ferroptosis, which is a novel form of programmed cell death and may play an effect on nonalcoholic steatohepatitis (NASH). However, the understanding of the mechanism is limited. Herein, our study aimed to explore the mechanism and role of HO-1 in NASH ferroptosis. Methods Hepatocyte conditional HO-1 knockout (HO-1HEPKO) C57BL/6J mice were established and fed a high-fat diet (HFD). Additionally, wild-type mice were fed either a normal diet or a HFD. Hepatic steatosis, inflammation, fibrosis, lipid peroxidation, and iron overload were assessed. AML12 and HepG2 cells were used to investigate the underlying mechanisms in vitro. Finally, liver sections from NASH patients were used to clinically validate the histopathology of ferroptosis. Results In mice, HFD caused lipid accumulation, inflammation, fibrosis, and lipid peroxidation, which were aggravated by HO-1HEPKO. In line with the in vivo results, HO-1 knockdown upregulated reactive oxygen species accumulation, lipid peroxidation, and iron overload in AML12 and HepG2 cells. Additionally, HO-1 knockdown reduced the GSH and SOD levels, which was in contrast to HO-1 overexpression in vitro. Furthermore, the present study revealed that the NF-κB signaling pathway was associated with ferroptosis in NASH models. Likewise, these findings were consistent with the liver histopathology results of NASH patients. Conclusion The current study showed that HO-1 could alleviate NASH progression by mediating ferroptosis.

Effects of Dityrosine on Lactic Acid Metabolism in Mice Gastrocnemius Muscle During Endurance Exercise via the Oxidative Stress-Induced Mitochondria Damage

“…74 Ho-1 possesses heme binding activity, heme oxygenase activity, and protein homodimerization activity. 75 It catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exhibiting significant antioxidant and antiinflammatory properties. 76 Nqo1 is a flavoprotein that catalyzes the two-electron reduction of quinone to hydroquinone using NADH, serving as a scavenger for ROS.…”

“…In the Nrf2/ARE signaling pathway, Gpx-1 encodes a protein that belongs to the glutathione peroxidase family, which catalyzes the reduction of hydroperoxides by glutathione, thereby protecting cells against oxidative stress . Ho-1 possesses heme binding activity, heme oxygenase activity, and protein homodimerization activity . It catalyzes the degradation of heme into biliverdin, free iron, and carbon monoxide, exhibiting significant antioxidant and anti-inflammatory properties .…”

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…In AML12 and HepG2 cells, HO-1 knockdown could accelerate ROS accumulation, lipid peroxidation, and iron overload. In contrast to HO-1 overexpression, HO-1 knockdown also decreased glutathione (GSH) and superoxide dismutase (SOD) levels in vitro [ 34 ]. This result may be associated with the HO-1 mediated-enhancement of glutathione peroxidase 4 (GPX4) activity [ 35 ].…”