Pharmacy and Pharmaceutical Sciences Commons^™

Fxr Acetylation Is Normally Dynamically Regulated By P300 And Sirt1 But Constitutively Elevated In Metabolic Disease States, Jongsook Kim Kemper, Zhen Xiao, Bhaskar Ponugoti, Ji Miao, Sungsoon Fang, Deepthi Kanamaluru, Stephanie Tsang, Shwu-Yuan Wu, Cheng-Ming Chiang, Timothy D. Veenstra

Pharmaceutical Sciences Faculty Publications

The nuclear bile acid receptor FXR is critical for regulation of lipid and glucose metabolism. Here, we report that FXR is a target of SIRT1, a deacetylase that mediates nutritional and hormonal modulation of hepatic metabolism. Lysine 217 of FXR is the major acetylation site targeted by p300 and SIRT1. Acetylation of FXR increases its stability but inhibits heterodimerization with RXRalpha, DNA binding, and transactivation activity. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes. Surprisingly, in mouse models of metabolic disease, FXR interaction with SIRT1 and p300 was dramatically altered, FXR acetylation levels were elevated, and overexpression …