The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Mol Aspects Med. 2017 Aug:56:34-44. doi: 10.1016/j.mam.2017.04.004. Epub 2017 May 5.

Abstract

Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies.

Keywords: Bile acids; Enterohepatic circulation; Farnesoid X receptor (FXR); Gut-liver crosstalk; Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH).

Publication types

  • Review

MeSH terms

  • Azepines / therapeutic use
  • Bile Acids and Salts / metabolism*
  • Bile Acids and Salts / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Disease Progression
  • Energy Metabolism / drug effects
  • Gene Expression Regulation
  • Glucose / metabolism
  • Humans
  • Indoles / therapeutic use
  • Isoxazoles / therapeutic use
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / etiology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Steroid / agonists
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism

Substances

  • 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
  • Azepines
  • Bile Acids and Salts
  • GPBAR1 protein, human
  • Indoles
  • Isoxazoles
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • Receptors, Steroid
  • WAY-362450
  • farnesoid X-activated receptor
  • Glucose
  • GW 4064