Journal article
Hepatocyte-specific Nrf2 deficiency mitigates high-fat diet-induced hepatic steatosis: Involvement of reduced PPARγ expression
Redox biology, Vol.30, pp.101412-101412
02/2020
DOI: 10.1016/j.redox.2019.101412
PMCID: PMC6940621
PMID: 31901728
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging global disease with increasing prevalence. However, the mechanism of NAFLD development is not fully understood. To elucidate the cell-specific role of nuclear factor erythroid-derived 2-like 2 (NRF2) in the pathogenesis of NAFLD, we utilized hepatocyte- and macrophage-specific Nrf2-knockout [Nrf2(L)-KO and Nrf2(Mϕ)-KO] mice to examine the progress of NAFLD induced by high-fat diet (HFD). Compared to Nrf2-LoxP littermates, Nrf2(L)-KO mice showed less liver enlargement, milder inflammation and less hepatic steatosis after HFD feeding. In contrast, Nrf2(Mϕ)-KO mice displayed no significant difference in HFD-induced hepatic steatosis from Nrf2-LoxP control mice. Mechanistic investigations revealed that Nrf2 deficiency in hepatocytes dampens the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its downstream lipogenic genes in the liver and/or primary hepatocytes induced by HFD and palmitate exposure, respectively. While PPARγ agonists augmented PPARγ expression and its transcriptional activity in primary hepatocytes in a NRF2-dependent manner, forced overexpression of PPARγ1 or γ2 distinctively reversed the decreased expression of their downstream genes fatty acid binding protein 4, lipoprotein lipase and/or fatty acid synthase caused by Nrf2 deficiency. We conclude that NRF2-dependent expression of PPARγ in hepatocytes is a critical initiating process in the development of NAFLD, suggesting that inhibition of NRF2 specifically in hepatocytes may be a valuable approach to prevent the disease.
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•Nrf2(L)-KO, but not Nrf2(Mϕ)-KO, mice showed lessened hepatic steatosis induced by HFD feeding.•Nrf2 deficiency dampened the expression and transcriptional activity of PPARγ in hepatocytes.•PPARγ agonists increased PPARγ expression/activity in hepatocytes in a NRF2-dependent manner.•OE of PPARγ partially reversed the reduction of lipogenic genes in Nrf2(L)-KO hepatocytes.
Details
- Title: Subtitle
- Hepatocyte-specific Nrf2 deficiency mitigates high-fat diet-induced hepatic steatosis: Involvement of reduced PPARγ expression
- Creators
- 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.Jingqi 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.Dan Liu - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.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.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.Chengjie Chen - Program of Environmental Toxicology, School of Public Health, China Medical University No 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.Junbo 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.Linlin Wang - School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR ChinaXin Wang - Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR ChinaRui Zhao - School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR ChinaHuihui Wang - China Medical UniversityMelvin E. Andersen - Research Triangle Park FoundationQiang Zhang - Emory UniversityYuanyuan Xu - China Medical UniversityJingbo Pi - 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
- Redox biology, Vol.30, pp.101412-101412
- DOI
- 10.1016/j.redox.2019.101412
- PMID
- 31901728
- PMCID
- PMC6940621
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81830099, 81573106, 81573187, 81402635; name: Shenyang Municipal Bureau of Science and Technology Support Program, award: RC180207; DOI: 10.13039/501100005047, name: Liaoning Province Natural Science Foundation, award: 20180530011; DOI: 10.13039/501100007300, name: China Medical University; DOI: 10.13039/501100007300, name: China Medical University; DOI: 10.13039/100014718, name: National Natural Science Fund, award: YQ20170001
- Language
- English
- Date published
- 02/2020
- Academic Unit
- Neurology
- Record Identifier
- 9984303021602771
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