Identification of Nogo-B as a new molecular target of peroxisome proliferator-activated receptor gamma

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a fast-growing chronic liver disease worldwide which can lead to liver cirrhosis. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, plays an important role in lipogenesis. Increased Nogo-B expression can be determined in the liver of cirrhosis patients. However, the effect of PPARγ activation on hepatic Nogo-B expression remains unknown. In this study, we found PPARγ activation by rosiglitazone or dephosphorylation increased Nogo-B expression at mRNA and protein levels in HepG2 cells and mouse primary hepatocytes. Furthermore, we identified a PPARγ response element (PPRE) in Nogo-B promoter and found PPARγ enhanced Nogo-B transcription in a PPRE-dependent manner. ChIP assay further confirms rosiglitazone enhanced the binding of PPARγ to Nogo-B promoter. Using a liver specific PPARγ deficient mice, we determined the critical role of PPARγ expression in regulating hepatic Nogo-B expression. Increased glucose and palmitate in culture medium activated Nogo-B and PPARγ expression in mouse primary hepatocytes, and corresponding, high-fat diet (HFD) induced fatty liver associated with increased hepatic Nogo-B and PPARγ expression in mice. Similarly, serum Nogo-B levels in patients with NAFLD were increased. However, rosiglitazone treatment reduced HFD-induced fatty liver and Nogo-B expression. In summary, our study identifies Nogo-B as a new molecular target of PPARγ, and suggests increased Nogo-B might be a potential indicator for NAFLD.

Keywords: Fatty liver; Gene expression; Nogo-B; Nuclear signaling; PPARγ; Rosiglitazone.