Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

Abstract

The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr(-/-) mice. We used chromatin immunoprecipitation-based genome-wide response element analyses coupled with luciferase reporter assays to identify functional FXR response elements within promoters, introns, or intragenic regions of these genes. Consistent with the observed transcriptional changes, FXR gene dosage is positively correlated with the degree of protection from APAP-induced hepatotoxicity in vivo. Further, we demonstrate that pretreatment of wild-type mice with an FXR-specific agonist provides significant protection from APAP-induced hepatotoxicity. Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP.

Fibroblast Growth Factor 19 Treatment Ameliorates Disruption of Hepatic Lipid Metabolism in Farnesoid X Receptor (Fxr)-Null Mice

“…Recent studies have indicated the protective role of FXR signaling in chemical-induced liver injury. [29][30][31] Because FGF15/19 signaling is up-regulated by FXR activation, it probably participates in the protection of hepatic function. The present study raises the possibility of application of the FGF19 signaling pathway to liver disorders, such as non-alcoholic fatty liver disease with insulin resistance, since Fxr-null mice seem to be models of the metabolic syndrome with hepatic steatosis.…”

Regulation of human class I alcohol dehydrogenases by bile acids

“…FXR has been shown to have relevance in the attenuation of clinically important conditions such as gallstone disease ( 11,12 ), cholestasis ( 13 ), and fatty liver disease ( 14 ). Most of these hepatoprotective functions of FXR can be attributed to the induction of genes involved in bile acid detoxifi cation and xenobiotic metabolism, including phase I oxidation enzyme CYP3A4 ( 15 ) and a number of phase II conjugation enzymes ( 16 ) and phase III effl ux transporters ( 10 ).…”

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

“…Upon bile acid binding, FXR positively regulates a series of genes responsible for maintaining normal liver physiology, thus protecting the hepatocyte from environmental insults (Huang et al, 2006;Lee et al, 2010a). In particular, CDCA is a major bile acid constituent that exerts a hepatoprotective effect by activating FXR.…”

“…FXR functions as a ligand-mediated transcription factor by binding to specific DNA motifs in the promoter regions of target genes, and it regulates the expression of various genes involved in bile acid, lipid, and glucose metabolism (Wang et al, 1999). FXR plays a role in the induction of genes encoding for proteins involved in xenobiotic metabolism and detoxification (Urquhart et al, 2007;Lee et al, 2010a). Bile acids are synthesized from cholesterol by a series of enzymatic reactions in hepatocytes and work as a digestive surfactant, promoting lipid absorption (Lefebvre et al, 2009).…”

“…Because FXR promotes hepatocyte survival (Lee et al, 2010a), we further explored the role of AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) activation by FXR in the phosphorylation of C/EBP␤ and its target gene induction. In this study, we report that the activation of FXR by CDCA contributes to the activating phosphorylation of C/EBP␤, which may be mediated by AMPK-dependent ERK1/2 activation.…”