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Heme oxygenase-1 regulates autophagy through carbon-oxygen to alleviate deoxynivalenol-induced hepatic damage
Zhao Peng1,2, Yuxiao Liao1,2, Xiaoqian Wang1,2
1Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Wuhan, 430030, China.
Abstract:
Deoxynivalenol (DON) cannot be totally removed due to its stable chemical characteristics and chronic exposure to low doses of DON causes significant toxic effects in humans and animals. However, the potential hazard of such low-dose exposure in target organs still remains not completely understood, especially in liver, which is mainly responsible for detoxification of DON. In the present study, we demonstrated for the first time that estimated human daily DON exposure (25 μg/kg bw) for 30 and 90 days caused low-grade inflammatory infiltration around hepatic centrilobular veins, elevated systemic IL-1β, IL-6 and TNF-α and impaired liver function evidenced by increased serum ALT activity. At the molecular level, expressions of autophagy-related proteins as well as Cleaved Caspase-3 and Cleaved Caspase-7 were upregulated during DON exposure, which indicated the activation of autophagy and apoptosis. Importantly, AAV-mediated liver-specific overexpression of HO-1 reversed DON-induced liver damages, upregulated autophagy and attenuated apoptosis in liver, while AAV-mediated HO-1 silence aggravated DON-induced liver damages, inhibited autophagy and increased apoptosis. Furthermore, in vitro experiments demonstrated that lentivirus-mediated HO-1 overexpression in Hepa 1-6 cells prolonged the duration of autophagy and delayed the onset of apoptosis. HO-1 silence in Hepa 1-6 cells inhibited activation of autophagy and accelerated occurrence of apoptosis, and these could be recovered by CO pre-treatment. Therefore, we suppose that HO-1 might be a potential research target to protect human and animal from liver injuries induced by low dose of DON exposure.
Insights
Chronic low-dose Deoxynivalenol (DON) exposure damages the liver, causing inflammation and impaired function. Heme oxygenase-1 (HO-1) activation protected against DON-induced liver injury by modulating autophagy and apoptosis.
Area of Science:
- Toxicology
- Hepatology
- Molecular Biology
Background:
- Deoxynivalenol (DON) is a stable mycotoxin with chronic low-dose exposure causing toxic effects.
- The liver's role in DON detoxification makes it a key target organ for understanding low-dose exposure hazards.
- Potential molecular mechanisms underlying DON-induced liver injury remain incompletely understood.
Purpose of the Study:
- To investigate the effects of chronic low-dose Deoxynivalenol (DON) exposure on liver function and molecular pathways.
- To explore the role of Heme oxygenase-1 (HO-1) in mitigating DON-induced liver damage.
- To elucidate the interplay between HO-1, autophagy, and apoptosis in the context of DON toxicity.
Main Methods:
- Animal models exposed to estimated human daily DON intake for 30 and 90 days.
- Assessment of liver function via serum ALT activity and histopathological examination.
- Molecular analysis of inflammatory cytokines (IL-1β, IL-6, TNF-α), autophagy-related proteins, and apoptosis markers (Cleaved Caspase-3, Cleaved Caspase-7).
- In vivo (AAV-mediated gene delivery) and in vitro (lentivirus-mediated gene delivery in Hepa 1-6 cells) manipulation of HO-1 expression.
- Carbon monoxide (CO) pre-treatment in vitro.
Main Results:
- DON exposure led to low-grade hepatic inflammation, elevated systemic inflammatory cytokines, and impaired liver function.
- DON exposure upregulated autophagy and apoptosis markers in the liver.
- HO-1 overexpression reversed DON-induced liver damage, promoted autophagy, and attenuated apoptosis.
- HO-1 silencing exacerbated DON-induced liver injury, inhibited autophagy, and increased apoptosis.
- In vitro, HO-1 overexpression prolonged autophagy and delayed apoptosis, while HO-1 silencing accelerated apoptosis, which was mitigated by CO.
Conclusions:
- Chronic low-dose DON exposure induces liver injury through inflammation, autophagy, and apoptosis pathways.
- Heme oxygenase-1 (HO-1) plays a protective role against DON-induced liver damage by modulating autophagy and apoptosis.
- HO-1 represents a potential therapeutic target for mitigating liver injuries caused by low-dose DON exposure.
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