Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91

Mette Trauelsen, Elisabeth Rexen Ulven, Siv A. Hjorth, Matjaz Brvar, Claudia Monaco, Thomas M. Frimurer, Thue W. Schwartz

 

Succinate functions not only as an energy source and building block but also as an extracellular messenger, signaling via the G-protein coupled receptor (GPCR) GPR91. Metabolic stress conditions cause the levels of succinate to rise, enabling activation of GPR91. The physiological role of GPR91 on whole body metabolism, however, is still unclear. Trauelsen and colleagues developed drug-like non-metabolite GPR91 agonists as potential pharmacological tools by using a receptor structure-based approach. The compounds they identified should make it possible to study effects of selective GPR91 activation in an in vivo setting after oral administration.

Objective: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice.

Methods: OCA and IP118 alone and in combination were sub-chronically administered to Lepob/Lepob mice with diet-induced NASH or diet-induced obese (DIO) mice. Metabolic (body weight and glucose) and liver (biochemical and histological) endpoints were assessed. NASH severity in Lepob/Lepob mice was graded using a customized integrated scoring system.

Results: OCA reduced liver weight and lipid in NASH mice (both by −17%) but had no effect on plasma ALT or AST levels. In contrast, IP118 significantly reduced liver weight (−21%), liver lipid (−15%), ALT (−29%), and AST (−27%). The combination of OCA + IP118 further reduced liver weight (−29%), liver lipid (−22%), ALT (−39%), and AST (−36%). Combination therapy was superior to monotherapies in reducing hepatic steatosis, inflammation, and fibrosis. Hepatic improvements with IP118 and OCA + IP118 were associated with reduced body weight (−4.3% and −3.5% respectively) and improved glycemic control in OCA + IP118-treated mice. In DIO mice, OCA + IP118 co-administration reduced body weight (−25.3%) to a greater degree than IP118 alone (−12.5%) and further improved glucose tolerance and reduced hepatic lipid.

Conclusions: Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.


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