A Dual Farnesoid X Receptor Agonist /Soluble Epoxide Hydrolase Inhibitor Prevents Non‐Alcoholic Steatohepatitis in Mice

Abstract

Non‐alcoholic steatohepatitis (NASH) is becoming the most prevalent metabolic liver disorder and is a serious global health burden. Farnesoid X receptor (FXR) agonists are in late stage clinical development to counter the disease and promise therapeutic efficacy. However, the multi‐factorial nature of NASH pathogenesis and progression indicate the need for a therapeutic approach that will target multiple pathophysiological aspects of NASH. We have developed a dual FXR agonist/soluble epoxide hydrolase (sEH) inhibitor (FXRA/sEHI) and investigated its ability to prevent NASH in toxin‐ and diet‐induced mouse NASH models. Toxin‐induced NASH was achieved in male C57BL/6 mice by injecting 200 μg streptozotocin (STZ) solution two days after birth and feeding a high‐fat diet after 4 weeks of age. Diet‐induced NASH was carried out in adult (8–12 weeks old) male C57BL/6J mice fed a methionine‐choline deficient diet (MCD; D518810) and was compared to mice fed a composition‐matched methionine‐choline replete control diet (D518754) for 4 weeks. In toxin‐induced NASH model, mice were orally treated with vehicle or FXRA/sEHI (10 mg/kg, thrice daily) or an FXR agonist obeticholic acid (OCA, 10 mg/kg, once daily) for 4 weeks. The mice from diet‐induced NASH model treated with FXRA/sEHI (10 mg/kg/d) or vehicle given in drinking water for 4 weeks. At the end of the 4‐week treatment period, blood was collected for biochemical analysis, liver tissue was collected for mRNA expression and histopathological analysis. Mice of the toxin‐induced NASH model had higher liver enzyme, hyperlipidemia, liver fibrosis, and steatosis. FXRA/sEHI treatment reduced these parameters (by 20–50%, P<0.05), while OCA displayed weak or no beneficial effect on NASH (P>0.05). In diet‐induced NASH model, the mice exhibited 2‐fold higher hepatic fibrosis, 2–6‐fold higher hepatic mRNA expressions of inflammatory and fibrotic markers, and marked hepatic steatosis (P<0.05). The dual modulator FXRA/sEHI robustly prevented hepatic steatosis, fibrosis, and inflammation (by 50–80%, P<0.05) compared to vehicle. Our results demonstrate strong potential for dual FXRA/sEHI modulators as a novel therapeutic strategy in NASH and advocate multi‐targeted approaches in NASH treatment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.