FXR Acetylation Is Normally Dynamically Regulated by p300 and SIRT1 but Constitutively Elevated in Metabolic Disease States

Abstract

Summary 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 RXRα, DNA binding, and transactivation activity. Down-regulation 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 of SIRT1 or resveratrol treatment reduced acetylated FXR levels. Our data demonstrate that FXR acetylation is normally dynamically regulated by p300 and SIRT1 but is constitutively elevated in metabolic disease states. Small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders.

Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

“…6E). In addition to regulation through the Sirt1-FXR pathway (20), the Sirt1-FoxO1 pathway also plays an important role in the regulation of the Nr0b2 gene expression. As an orphan nuclear receptor, Nr0b2 has been shown to inhibit numerous nuclear receptors and transcription factors, including HNF-4␣, CREB, and FoxO1 (4,5,23,33,47).…”

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

“…Previous studies reported that the activation of SIRT1 by resveratrol substantially decreased the acetylated FXR levels in the livers of ob/ob mice. In addition, treatment with resveratrol significantly decreased the Shp mRNA levels and elevated the bile acid pool sizes in mice [38] . Our results confirmed that resveratrol enhanced the expression of transporters and enzymes correlated with elevated FXR levels in vivo.…”

Transcriptional Co-activator p300 Maintains Basal Hepatic Gluconeogenesis

“…Through these domains, p300 and CBP interact with basal transcription factors and RNA polymerase II as well as a variety of other transcription factors to function as scaffold proteins facilitating interactions among the basal transcription machinery and upstream transcription factors (8 -11). The histone acetyltransferase activity of p300 and CBP modifies histones leading to chromatin remodeling and transcriptional activation; p300 and CBP also acetylate other proteins such as FXR, SREBP-1, CRTC2, and FOXO1, leading to the changes of genes related to glucose and lipid metabolism (12)(13)(14)(15). Gene alterations in CBP and p300 cause various diseases such as Rubinstein-Taybi syndrome and leukemia (8, 16 -18).…”