Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury.

Anca D Petrescu,Sharon Demorrow

doi:10.3390/cells10081846

Abstract

Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.

Highlights

In this review we focus on Farnesoid X receptor (FXR) since it is the main player in dysregulation of bile acids (BA) homeostasis in the context of cholestatic injury of the liver
It was established that rifampicin, is a drug that upregulates the expression of detoxification enzymes involved in BA metabolism [41,47,89]
This study suggests that several targets including AMPK, nuclear factor E2-related factor 2 (NRF2), autophagy regulators and FXR are to be considered for developing novel therapies for liver cholestatis and fibrosis

Summary

Introduction

Cholestasis can be caused by mutations of genes encoding for proteins with roles in bile transport from hepatocytes into cholangiocytes and bile ducts, resulting in the retention of BA in the liver. Known therapies as well as new potential drug targets from mechanistic studies on cholestasis-induced liver fibrosis, with focus on dysfunctions in metabolism and transport of hydrophobic BA, are outlined. FXR mediates the bile formation and flow from the liver to the gallbladder by upregulating bile salt export pump (BSEP, ABCB11) which exports BA from hepatocytes; multidrug resistance associated 2 (MRP2, ABCC2) for the transport of BA amongst many other components of the bile into the gallbladder.

Targeting FXR for BA Regulation in Cholestasis

Targeting FXR in Portal Hypertension Associated with Cholestasis-Induced

FXR Involvement in Autophagy during Cholestasis

Findings

Conclusions