Therapeutic targets for cholestatic liver injury

Abstract

Introduction: Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury.

Areas covered: This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact.

Expert opinion: While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients.

Keywords:

• bile acid toxicity
• inflammation
• innate immunity
• neutrophils
• obstructive cholestasis

Article highlights.

• Cholestasis results in elevated bile acid levels in multiple tissue compartments.

• Hydrophobic bile acids may directly cause injury to hepatocytes and other cells at biliary (millimolar) concentrations; this effect is species-dependent.

• Neutrophil recruitment and neutrophil mediated liver injury are common sequelae in cholestatic liver injury.

• Bile acids themselves may be pro-inflammatory molecules at high concentrations.

• A number of different therapeutic targets including nuclear receptors, G-protein-coupled cell surface receptors and more have been identified that may alter bile acid-induced signaling.

  This box summarizes key points contained in the article.

Declaration of interest

The authors were supported by Clinical and Translational Science Award (CTSA) number UL1TR000001 (formerly UL1RR033179) from the National Center for Advancing Translational Sciences (NCATS) awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research. In addition, H Jaeschke was supported in part by the National Institutes of Health under grants R01 DK070195 and R01 AA12916, and by grants from the National Center for Research Resources (P20 RR021940) and the National Institute of General Medical Sciences (P20 GM103549) of the National Institutes of Health. BL Woolbright received support from the “Training Program in Environmental Toxicology” T32 ES007079 from the National Institute of Environmental Health Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the Foundation for the National Institutes of Health: [Grant Number 123-4567]; The Warren Foundation: [Grant Numbers 190914, 220914].