Bile Acid Receptor Activation Modulates Hepatic Monocyte Activity and Improves Nonalcoholic Fatty Liver Disease
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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.
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Simultaneous activation of FXR and TGR5 resulted in intrahepatic accumulation of Ly6Clow monocytes, which subsequently differentiated into anti-inflammatory macrophages.
“Mcmahan et al. found that simultaneous activation of FXR and TGR5 resulted in intrahepatic accumulation of Ly6Clow monocytes, which subsequently differentiated into anti-inflammatory macrophages [79].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [79]
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- Authors
- McMahan, R. H., Wang, X. X., Cheng, L. L., Krisko, T., Smith, M., El Kasmi, K., Pruzanski, M., Adorini, L., Golden-Mason, L., Levi, M., & Rosen, H. R.
- Affiliations
- University of Colorado Anschutz (US)
- Brigham and Women's Hospital (US)
- Mayo Clinic in Arizona (US)
- Intercept Pharmaceuticals (United States) (US)
- National Jewish Health (US)
- Corresponding author
- Rosen, Hugo R.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 288
- Issue
- 17
- Pages
- 11761-11770
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3636865
- OpenAlex
- W2120910422
- Cited by
- 225
- References
- 50
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 14 · 2022: 24 · 2021: 20 · 2020: 19 · 2019: 17 · 2018: 25 · 2017: 24 · 2016: 11 · 2015: 15 · 2014: 22 · 2013: 7
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001954)
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (K24AI083742, U19 AI1066328)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK096025, R01DK098336, P30DK048520)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- non-alcoholic fatty liver disease, bile acid receptors, farnesoid X receptor, TGR5, G protein-coupled bile acid receptor, macrophage polarization, Ly6C, M2 macrophages, IL-10, cAMP signaling, db/db mice, liver inflammation
- MeSH terms
- Mannose Receptor, Receptor, Farnesoid X-Activated, Cyclic AMP, Animals, Fatty Liver, Gene Expression Regulation, Humans, Liver, Macrophage Activation, Macrophages, Male, Mice, Obese, Monocytes, Receptors, Cell Surface, Interleukin-10, Receptors, Cytoplasmic and Nuclear, Intercellular Signaling Peptides and Proteins, Lectins, C-Type, Mannose-Binding Lectins, Receptors, G-Protein-Coupled, Mice, Non-alcoholic Fatty Liver Disease
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