Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression

Jialing Ma; Peng Zeng; Lipei Liu; Mengmeng Zhu; Juan Zheng; Chengyi Wang; Xiaokang Zhao; Wenquan Hu; Xiaoxiao Yang; Yajun Duan; Jihong Han; Qing R Miao; Yuanli Chen

doi:10.3389/fphar.2021.817784

Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression

Front Pharmacol. 2022 Jan 17:12:817784. doi: 10.3389/fphar.2021.817784. eCollection 2021.

Authors

Jialing Ma¹, Peng Zeng², Lipei Liu², Mengmeng Zhu¹, Juan Zheng¹, Chengyi Wang¹, Xiaokang Zhao¹, Wenquan Hu³, Xiaoxiao Yang¹, Yajun Duan¹, Jihong Han^{1

2}, Qing R Miao⁴, Yuanli Chen¹

Affiliations

¹ Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
² College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
³ Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, China.
⁴ Diabetes and Obesity Research Center, New York University Long Island School of Medicine, New York, NY, United States.

Abstract

Increased Nogo-B receptor (NGBR) expression in the liver improves insulin sensitivity by reducing endoplasmic reticulum stress (ER stress) and activating the AMPK pathway, although it remains elusive the mechanisms by which NGBR is induced. In this study, we found that PPARγ ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPARγ-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPARγ deficient (PPARγ^LKO) mice, we identified the key role of PPARγ expression in pioglitazone-induced NGBR expression. Meanwhile, the basal level of ER stress and inflammation was slightly increased by NGBR knockdown. However, the inhibitory effect of rosiglitazone on inflammation was abolished while rosiglitazone-inhibited ER stress was weakened by NGBR knockdown. Taken together, these findings show that NGBR is a previously unrecognized target of PPARγ activation and plays an essential role in PPARγ-reduced ER stress and inflammation.

Keywords: ER stress; NGBR; PPARγ; inflammation; rosiglitazone.