Journal article
Liver-specific Nrf2 deficiency accelerates ethanol-induced lethality and hepatic injury in vivo
Toxicology and applied pharmacology, Vol.426, pp.115617-115617
09/01/2021
DOI: 10.1016/j.taap.2021.115617
PMID: 34116071
Abstract
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality from liver disorders. Various mechanisms, including oxidative stress and impaired lipid metabolism, have been implicated in the pathogenesis of ALD. Our previous studies showed that nuclear factor erythroid-derived 2-like 2 (Nrf2) is a master regulator of adaptive antioxidant response and lipid metabolism by using a liver-specific Nrf2 knockout (Nrf2(L)-KO) mouse model. In the current study, an ALD model was developed by a Lieber-DeCarli liquid-based ethanol diet given to this Nrf2(L)-KO mouse strain. We found that Nrf2(L)-KO mice were quite sensitive to lethality from 6.3% ethanol diet. We thus decreased the ethanol concentration to 4.2% to obtain tissues to analyze the role of hepatic Nrf2 in the development of ALD. We found that mild hepatic steatosis occurred with both liquid control and 4.2% ethanol diet feeding, which contain 35% fat. Both the fatty acid β-oxidation marker peroxisome proliferators-activated receptor α (PPARα), and lipogenesis regulator PPARγ were reduced with ethanol feeding in Nrf2(L)-KO mice, compared to Nrf2 floxed control mice (Nrf2-LoxP). However, Nrf2(L)-KO livers showed more cell injury than the livers of Nrf2-LoxP mice. Consistent with these data, there was increased proportion of apoptotic cells in the liver of ethanol-fed Nrf2(L)-KO mice comparing Nrf2-LoxP controls. Mechanistically, Nrf2 mediated expression of ethanol detoxification enzymes, such as alcohol dehydrogenase 1 and aldehyde dehydrogenase1a1, likely contributed to the sensitivity to ethanol toxicity. In conclusion, hepatic Nrf2 is critical to the development of ALD, particularly the morbidity and liver injury.
•Nrf2(L)-KO mice are sensitive to ethanol-caused lethality.•Hepatic β-oxidation and lipogenesis are reduced in ethanol feeding Nrf2(L)-KO mice.•Nrf2(L)-KO livers have more cell injury after ethanol feeding.•Hepatic Nrf2 mediates ethanol detoxification genes induction.
Details
- Title: Subtitle
- Liver-specific Nrf2 deficiency accelerates ethanol-induced lethality and hepatic injury in vivo
- Creators
- Jing Sun - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Zhixuan Hong - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Shuai Shao - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Lu Li - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Bei Yang - Department of Histology and Embryology, School of Basic Medical Sciences, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, PR China.Yongyong Hou - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Huihui Wang - China Medical UniversityYuanyuan Xu - China Medical UniversityQiang Zhang - Emory UniversityJingbo Pi - China Medical UniversityJingqi Fu - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.426, pp.115617-115617
- DOI
- 10.1016/j.taap.2021.115617
- PMID
- 34116071
- NLM abbreviation
- Toxicol Appl Pharmacol
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 09/01/2021
- Academic Unit
- Neurology
- Record Identifier
- 9984303016902771
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