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

Abstract

ObjectiveNonalcoholic 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.MethodsOCA 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.ResultsOCA 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.ConclusionOur data suggest a complementary or synergistic therapeutic effect of GLP-1R and FXR agonism in mouse models of metabolic disease and NASH.

Tropifexor‐Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With the Antioxidative Gene Expression Profile in Rodents

“…Consequently, extracellular matrix deposition and fibrosis were also slightly reduced in OCA‐treated mice. These results are consistent with reports in which OCA alone was not able to completely reduce steatosis, inflammation, and fibrosis in AMLN‐fed mice …”

“…By contrast, vehicle‐ and OCA‐treated mice showed similar plasma levels of ALT and AST in NASH mice. This finding agrees with reports that showed that OCA failed to reduce the levels of circulating liver enzymes in HFD‐fed rodent models of NASH …”

“…Importantly, tropifexor decreased fibrosis in a dose‐dependent manner as revealed by trichrome staining and normalization of mRNA levels of the fibrotic markers Col1a1 and Timp1 in tropifexor‐treated NASH animals compared to control animals. In this context, OCA is the only other FXR agonist to have recently shown improvement in NAS, steatosis, ballooning, and histologic markers of NASH in Lep obese [ ob ]/ ob mice maintained on the AMLN diet but not on the purely dietary AMLN model …”

Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

“…OCA is a first-in-class semisynthetic bile acid exerting its effect by binding to the nuclear farnesoid X receptor (FXR), thereby activating several regulators in bile acid synthesis and transport, hepatic lipid, and carbohydrate metabolism as well as immune function [ 32 – 35 ]. OCA attenuates hepatic inflammation and reduces low-grade hepatocyte ballooning and has recently been reported to reduce liver pathology in obese mouse models of NASH [ 13 , 36 – 38 ]. Elafibranor is a high-affinity agonist for the nuclear peroxisome proliferator-activated alpha/delta receptor (PPAR-α/δ) and ameliorates NASH mainly by increasing the disposal of hepatic fatty acid as well as inhibiting pathways involved in inflammation and fibrosis [ 13 , 39 , 40 ].…”

Glucagon-like Peptide-1 (GLP-1)

“…Preclinical studies have evaluated the therapeutic potential of GLP-1 based polypharmacology for the treatment of obesity and diabetes. The various approaches include the combination of GLP-1R agonists with leptin [912,913], salmon calcitonin [914], PYY [915], CCK [916], insulin [917], adrenomedullin [918], and b3-adrenergic receptor agonists [919], and antagonists at the cannabinoid receptor 1 (CB1) [920], or agonists at the receptors for melanocortin-4 (MC4R) [685] or farnesoid-x (FXR) [921]. In summary, a series of GLP-1-based combination therapies has been found to offer metabolic benefits greater than what is achieved by treatment with each compound alone.…”