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

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 PPAR gamma ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPAR gamma-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPAR gamma deficient (PPAR gamma(LKO)) mice, we identified the key role of PPAR gamma 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 PPAR gamma activation and plays an essential role in PPAR gamma-reduced ER stress and inflammation.

Automated summary

This study found that PPAR gamma ligands can enhance the expression of NGBR in the liver and reduce ER stress and inflammation by selectively activating PPAR gamma. These findings reveal the potential mechanism of NGBR in regulating insulin sensitivity.