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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.

Author information

1
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
2
Division of Pediatric Gastroenterology, Children's Hospital Los Angeles, Los Angeles, California, USA.
3
Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.
4
Center for Neurotherapeutics Discovery and Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
5
Department of Pediatrics, University of Cincinnati, Cincinnati Ohio, USA.

Abstract

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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