A dual farnesoid X receptor/soluble epoxide hydrolase modulator treats non-alcoholic steatohepatitis in mice

• Published in: Biochemical pharmacology 2019-08, Vol.166, p.212-221
• Main Authors: Hye Khan, Md. Abdul, Schmidt, Jurema, Stavniichuk, Anna, Imig, John D., Merk, Daniel
• Format: Article
• Language: English
• Subjects: Animals; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - pharmacology; Chenodeoxycholic Acid - therapeutic use; Diet, High-Fat - adverse effects; Dose-Response Relationship, Drug; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Male; Mice; Mice, Inbred C57BL; Multi-target ligand; NASH; Non-alcoholic fatty liver; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Partial FXR agonist; Polypharmacology; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2019.05.023

[Display omitted] Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the most prevalent metabolic liver disorders and a serious global health burden. NAFLD/NASH pathogenesis and progression are highly multi-factorial and likely demand a combination of multiple mechanisms to provide a more effective treatment. We have developed a dual farnesoid X receptor agonist (FXRA)/soluble epoxide hydrolase inhibitor (sEHi) to simultaneously address two validated and complementary modes of action in NASH treatment. Here we report the in vivo profiling for this FXRA/sEHi in toxin- and diet-induced rodent NASH models. In streptozotocin-induced NASH as a proof-of-concept study, the experimental FXRA/sEHi drug robustly prevented hepatic steatosis and fibrosis, and improved lipid homeostasis as well as biochemical markers of liver health. In methionine-choline-deficient high-fat diet-induced NASH, FXRA/sEHi treatment reduced hepatic steatosis and fibrosis to levels similar to healthy animals and demonstrated anti-inflammatory activity confirming that dual FXRA/sEHi modulation produces a triad of complementary anti-NASH effects. Our results validate dual FXRA/sEHi modulation as an effective therapeutic strategy to treat NASH and advocates for a combinational drug therapeutic approach for multifactorial liver diseases.