USP15 regulates lipid accumulation in hepatocyte through FABP4 and PPARγ dependent mechanism

Abstract

The Ubiquitin Specific Peptidase 15 (USP15) is an enzyme that is encoded by the USP15 gene. USP15 is a hydrolase that removes conjugated ubiquitin from target proteins. It regulates various pathways such as TGF-β receptor signaling and NF-κB pathways. Especially, USP15 acts as a key regulator of TGF-beta receptor signaling pathway and promotes deubiquitination of R-SMADs. Therefore, it alleviates inhibition of R-SMADs and promotes activation of TGF-β target genes. There have been a number of USP15 studies as to cancer and cancer immunology. However, correlation between USP15 and metabolic diseases is poorly understood. In this study, we demonstrate that considerably high expression level of USP15 in liver of healthy obese and steatosis patients. Also, we confirmed expression level of USP15 is up-regulated liver tissue of high fat diet fed C57BL/6 wild type mice and palmitic acid treated mouse hepatocyte cell line. Knock down of USP15 expression retarded lipid accumulation in mouse hepatocyte and expression of non alcoholic fatty liver diseases (NAFLD) related factors such as FABP4, perilipin and PPARγ. In contrast, overexpression of mUSP15 increased lipid accumulation in mouse hepatocyte and expression of NAFLD related factors. We also confirmed that liver tissue specific USP15 KO mice have less hepatic lipid accumulation than that of USP15 WT although PPARγ is overexpressed in liver.Moreover, we determined that USP15 interacted with FABP4 and PPARγ and then up-regulated their protein expressions. Additionally, we identified that up-regulated protein stabilty of FABP4 and PPARγ was due to retardation of ubiquitination of FABP4 and PPARγ by USP15. Taken together, USP15 induces deubiquitination of NAFLD associated factors and protein stability of them is upregulated. We proposed that USP15 has positive role of lipid accumlation in hepatocyte and ablation of USP15 expression prohibits NAFLD.