24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ

Christoph Grander; Moritz Meyer; Daniel Steinacher; Thierry Claudel; Bela Hausmann; Petra Pjevac; Felix Grabherr; Georg Oberhuber; Manuel Grander; Natascha Brigo; Almina Jukic; Julian Schwärzler; Günter Weiss; Timon E Adolph; Michael Trauner; Herbert Tilg

doi:10.1016/j.jhepr.2023.100872

24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ

JHEP Rep. 2023 Aug 3;5(11):100872. doi: 10.1016/j.jhepr.2023.100872. eCollection 2023 Nov.

Authors

Christoph Grander¹, Moritz Meyer¹, Daniel Steinacher², Thierry Claudel², Bela Hausmann^{3

4}, Petra Pjevac^{3

5}, Felix Grabherr¹, Georg Oberhuber⁶, Manuel Grander⁷, Natascha Brigo⁷, Almina Jukic¹, Julian Schwärzler¹, Günter Weiss⁷, Timon E Adolph¹, Michael Trauner², Herbert Tilg¹

Affiliations

¹ Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria.
² Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
³ Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria.
⁴ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁵ Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria.
⁶ INNPATH, Tirol-Kliniken University Hospital Innsbruck, Innsbruck, Austria.
⁷ Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria.

Abstract

Background & aims: Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD.

Methods: NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems.

Results: NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1β, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation.

Conclusions: NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD.

Impact and implications: Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.

Keywords: Alcoholic liver disease; M2 macrophages; Microbiota; Ppar-gamma; norUDCA.

Abstract

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