Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.
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.


CONCLUSION
Our data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.
['Jouihan|Hani|H|', 'Will|Sarah|S|', 'Guionaud|Silvia|S|', 'Boland|Michelle L|ML|', 'Oldham|Stephanie|S|', 'Ravn|Peter|P|', 'Celeste|Anthony|A|', 'Trevaskis|James L|JL|']
D000818:Animals D002635:Chenodeoxycholic Acid D004195:Disease Models, Animal D000067757:Glucagon-Like Peptide-1 Receptor D008103:Liver Cirrhosis D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008820:Mice, Obese D065626:Non-alcoholic Fatty Liver Disease D009765:Obesity D011897:Random Allocation D018160:Receptors, Cytoplasmic and Nuclear D015431:Weight Loss
Steatosis Fibrosis NASH OCA Combination therapy GLP-1