title: Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease.
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.
authors: Division of Gastroenterology, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors: Rachel H
authors: RH
authors: McMahan
authors: Xiaoxin X
authors: XX
authors: Wang
authors: Lin Ling
authors: LL
authors: Cheng
authors: Tibor
authors: T
authors: Krisko
authors: Maxwell
authors: M
authors: Smith
authors: Karim
authors: K
authors: El Kasmi
authors: Mark
authors: M
authors: Pruzanski
authors: Luciano
authors: L
authors: Adorini
authors: Lucy
authors: L
authors: Golden-Mason
authors: Moshe
authors: M
authors: Levi
authors: Hugo R
authors: HR
authors: Rosen
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D005234:Fatty Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008820:Mice, Obese; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000276:immunology / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000242:Cyclic AMP; D036341:Intercellular Signaling Peptides and Proteins; D016753:Interleukin-10; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C513561:Gpbar1 protein, mouse; C556062:IL10 protein, mouse; C413576:Retnla protein, mouse