The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice

Anna Kiepura; Maciej Suski; Kamila Stachyra; Katarzyna Kuś; Klaudia Czepiel; Anna Wiśniewska; Magdalena Ulatowska-Białas; Rafał Olszanecki

doi:10.1007/s10557-023-07430-7

The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice

Cardiovasc Drugs Ther. 2023 Jan 27. doi: 10.1007/s10557-023-07430-7. Online ahead of print.

Authors

Anna Kiepura¹, Maciej Suski¹, Kamila Stachyra¹, Katarzyna Kuś¹, Klaudia Czepiel¹, Anna Wiśniewska¹, Magdalena Ulatowska-Białas², Rafał Olszanecki³

Affiliations

¹ Department of Pharmacology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland.
² Department of Pathomorphology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland.
³ Department of Pharmacology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland. rafal.olszanecki@uj.edu.pl.

PMID: 36705799
DOI: 10.1007/s10557-023-07430-7

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo.

Methods: The effect of TUG-891 on fatty liver was investigated in apoE^-/- mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods.

Results: Treatment with TUG-891 inhibited the progression of liver steatosis in apoE^-/- mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx).

Conclusion: Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD.

Keywords: FFAR4/GPR120; Nonalcoholic fatty liver disease; Steatohepatitis; TUG-891.