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

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

doi:10.3389/fphar.2021.817784

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 (PPARγLKO) 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.

Highlights

The endoplasmic reticulum (ER) is an essential multifunctional organelle, which is the primary place for protein synthesis, folding, and assembly, as well as degradation of misfolded or damaged proteins
In line with increased Proliferator-activated receptor gamma (PPARγ) expression, Nogo-B receptor (NGBR) protein expression was increased by rosiglitazone in a concentration-dependent manner (Figure 1A)
We found that rosiglitazone-stimulated NGBR protein and mRNA expression in human umbilical vein endothelial cells (HUVECs) and HepG2 cells were significantly reduced by the PPARγ-specific blocker GW9662 (Figures 1E,F), indicating these effects on NGBR expression were mediated by the PPARγ signaling pathway

Summary

Introduction

The endoplasmic reticulum (ER) is an essential multifunctional organelle, which is the primary place for protein synthesis, folding, and assembly, as well as degradation of misfolded or damaged proteins. PPARγ Induces NGBR Expression cellular transcription and translation, as well as degradation pathways to resolve defects in protein folding These effects are accomplished by activating three transmembrane ER proteins, namely protein kinase RNA-dependent ER kinase (PERK), inositol-requiring enzyme 1 (IRE-1), and activating transcription factor 6 (ATF6) (Hetz, 2012). ER stress links to many inflammatory and stress signaling, including the activation of the nuclear factor κB (NF-κB) pathway (Kharroubi et al, 2004). Both inflammation and ER stress are short-term adaptive systems that are indispensable for the function and survival of the organism (Hotamisligil, 2010). ER stress can strengthen many stress and inflammatory signal pathways, aggravate metabolic disorders, and lead to obesity, insulin resistance, NAFLD, and dyslipidemia (Wang and Kaufman, 2012)

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Conclusion