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

• Published in: Redox biology Vol. 30; p. 101412
• Main Authors: Li, Lu, Fu, Jingqi, Liu, Dan, Sun, Jing, Hou, Yongyong, Chen, Chengjie, Shao, Junbo, Wang, Linlin, Wang, Xin, Zhao, Rui, Wang, Huihui, Andersen, Melvin E., Zhang, Qiang, Xu, Yuanyuan, Pi, Jingbo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020; Elsevier
• Subjects: Animals; Diet, High-Fat - adverse effects; Disease Models, Animal; Gene Expression Regulation - drug effects; Gene Knockout Techniques; Hepatocyte; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; High-fat diet; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; NALFD; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Nrf2; Organ Specificity; Palmitates - adverse effects; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Research Paper; Hepatocyte; Nrf2; High-fat diet; NALFD; PPARγ
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101412

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. [Display omitted] •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.