Glycoprotein nonmetastatic melanoma protein B is regulated by hepatic peroxisome proliferator-activated receptor γ in liver steatosis.

Hepatic glycoprotein nonmetastatic melanoma protein B (GPNMB) and nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) play essential roles in lipid metabolism. This study aimed to examine the molecular mechanism through which PPARγ controls GPNMB expression in liver steatosis. A microarray database was used to examine the gene expression patterns associated with fatty liver in type 2 diabetic leptin-deficient (ob/ob) mice, as well as in patients with non-alcoholic fatty liver disease (NAFLD) and advanced NAFLD. GPNMB expression significantly increased in the fatty livers of humans and mice. Elevated Gpnmb expression was notably reduced by liver-specific Pparγ knockout (PPARγLKO) in ob/ob mice. Similarly, alcohol-fed mice had increased hepatic Gpnmb levels. Transcriptomic analysis of the human liver samples revealed that Gpnmb expression was markedly higher in patients with fatty liver diseases, including those with NAFLD and alcoholic fatty liver disease, than in controls. Reporter and electrophoretic mobility shift assays confirmed that PPARγ directly enhances Gpnmb transcription via three functional PPARγ-responsive elements within the first intron. In conclusion, these findings suggest that Gpnmb is a novel PPARγ target in liver steatosis.