Differential Therapeutic Effects of FXR Activation, sEH Inhibition, and Dual FXR/sEH Modulation in NASH in Diet-Induced Obese Mice

Nonalcoholic fatty liver disease (NAFLD) is an epidemic chronic liver disease and may progress over nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma. The multiple metabolic, environmental, and genetic factors that are involved in NAFLD/NASH pathogenesis and progression suggest a need for multimechanistic interventions. We have developed and preliminarily characterized a concept of dual farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH) modulation as a promising polypharmacological strategy to counteract NASH. Here we report the profiling of FXR activation, sEH inhibition, and simultaneous FXR/sEH modulation as an interventional treatment in pre-established NASH in mice with diet-induced obesity (DIO). We found that full FXR activation was required to obtain antisteatosis effects but also worsened ballooning degeneration and fibrosis. In contrast, sEH inhibition and dual FXR/sEH modulation, despite a lack of antisteatosis activity, had anti-inflammatory effects and efficiently counteracted hepatic fibrosis. These results demonstrate great therapeutic potential of sEH inhibition to counteract hepatic fibrosis and validate the designed polypharmacology concept of dual FXR/sEH modulation as a potentially superior avenue for the effective treatment of the multifactorial condition NASH.