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JCI Insight. 2017 Aug 3;2(15). pii: 94488. doi: 10.1172/jci.insight.94488. [Epub ahead of print]

Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis.

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Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Division of Pediatric Gastroenterology, Children's Hospital Los Angeles, Los Angeles, California, USA.
Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
Center for Neurotherapeutics Discovery and Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
Department of Pediatrics, University of Cincinnati, Cincinnati Ohio, USA.


With the increase in obesity worldwide, its associated comorbidities, including nonalcoholic steatohepatitis (NASH), have become a public health problem that still lacks effective therapy. We have previously reported that mixed-lineage kinase 3-deficient (MLK3-deficient) mice are protected against diet-induced NASH. Given the critical need to identify new therapeutic agents, we sought to examine whether the small-molecule MLK3 inhibitor URMC099 would be effective in reversing diet-induced murine NASH. C57BL/6J mice were fed either a diet high in saturated fat, fructose, and cholesterol (FFC), or a chow diet for 24 weeks. Mice were treated with either URMC099 (10 mg/kg) twice daily by intraperitoneal injection or its vehicle during the last 2 weeks of the feeding study. FFC-fed mice receiving URMC099 had similar body weight, caloric intake, homeostatic model assessment of insulin resistance, metabolic phenotype, and hepatic steatosis compared with vehicle-treated mice. Furthermore, FFC-fed mice treated with URMC099 had less hepatic macrophage infiltration, activation, and proinflammatory polarization, as well as less liver injury and fibrosis when compared with vehicle-treated mice. In conclusion, URMC099 is well tolerated in mice without obvious toxicities and appears to be efficacious in reversing diet-induced NASH. Hence, URMC099 may serve as a therapeutic agent in human NASH.

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