Hepatocyte-specific Nrf2 deficiency mitigates high-fat diet-induced hepatic steatosis: Involvement of reduced PPAR gamma expression

• Type of Material: Article
• Authors: Lu Li, Emory University; Jingqi Fu, China Medical University; Dan Liu, China Medical University; Jing Sun, China Medical University; Yongyong Hou, China Medical University; Chengjie Chen, China Medical University; Junbo Shao, China Medical University; Linlin Wang, China Medical University; Xin Wang, China Medical University; Rui Zhao, China Medical University; Huihui Wang, China Medical University; Melvin E. Andersen, ScitoVat LLC; Qiang Zhang, Emory University; Yuanyuan Xu, China Medical University; Jingbo Pi, China Medical University
• Language: English
• Date: 2020-02-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.redox.2019.101412
• Title of Journal or Parent Work: Redox Biology
• Volume: 30
• Start Page: 101412
• End Page: 101412
• Grant/Funding Information: This work was supported by National Natural Science Foundation of China 81830099 (J.P.), 81573106 (J.P.), 81573187 (Y.X.) and 81402635 (J.F.), Shenyang Municipal Bureau of Science and Technology Support Program for Young Innovation Scholar (RC180207, J.F.); Liaoning Province Natural Science Foundation (20180530011, J.F.), the Startup Funding of China Medical University (J.P.), Liaoning Pandeng Scholar Program (J.P.), China Medical University Training Program for National Natural Science Fund for Excellent Young Scholars (YQ20170001, J.F.).
• Keywords: Cells; Redox; NALFD; Liver-disease; Steatohepatitis; Science & Technology; PPAR gamma; Oxidative stress; Deletion; High-fat diet; Life Sciences & Biomedicine; Nrf2; Inflammation; Enzymes; Hepatocyte; Mice; Biochemistry & Molecular Biology; Induced obesity
• Research Categories: Biology, Cell; Biology, Molecular; Chemistry, Biochemistry; Health Sciences, Nutrition

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.