Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease Academic Article uri icon

Overview

MeSH Major

  • Fatty Liver
  • Liver
  • Monocytes
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled

abstract

  • Nonalcoholic fatty liver disease (NAFLD) affects a large proportion of the American population. The spectrum of disease ranges from bland steatosis without inflammation to nonalcoholic steatohepatitis and cirrhosis. Bile acids are critical regulators of hepatic lipid and glucose metabolism and signal through two major receptor pathways: farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, and TGR5, a G protein-coupled bile acid receptor (GPBAR1). Both FXR and TGR5 demonstrate pleiotropic functions, including immune modulation. To evaluate the effects of these pathways in NAFLD, we treated obese db/db mice with a dual FXR/TGR5 agonist (INT-767) for 6 weeks. Treatment with the agonist significantly improved the histological features of nonalcoholic steatohepatitis. Furthermore, treatment increased the proportion of intrahepatic monocytes with the anti-inflammatory Ly6C(low) phenotype and increased intrahepatic expression of genes expressed by alternatively activated macrophages, including CD206, Retnla, and Clec7a. In vitro treatment of monocytes with INT-767 led to decreased Ly6C expression and increased IL-10 production through a cAMP-dependent pathway. Our data indicate that FXR/TGR5 activation coordinates the immune phenotype of monocytes and macrophages, both in vitro and in vivo, identifying potential targeting strategies for treatment of NAFLD.

publication date

  • April 26, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3636865

Digital Object Identifier (DOI)

  • 10.1074/jbc.M112.446575

PubMed ID

  • 23460643

Additional Document Info

start page

  • 11761

end page

  • 70

volume

  • 288

number

  • 17