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Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis
Kyoko Tomita1, Rohit Kohli2, Brittany L MacLaurin1
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, 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.
Insights
The mixed-lineage kinase 3 (MLK3) inhibitor URMC099 effectively reversed nonalcoholic steatohepatitis (NASH) in mice. This small molecule reduced liver inflammation and fibrosis, offering a potential new therapy for NASH.
Area of Science:
- Hepatology
- Pharmacology
- Metabolic Diseases
Background:
- Obesity and its comorbidities, like nonalcoholic steatohepatitis (NASH), are significant global health concerns.
- Current NASH therapies are limited, necessitating the development of novel treatments.
- Previous studies indicated mixed-lineage kinase 3 (MLK3)-deficient mice are protected from diet-induced NASH.
Purpose of the Study:
- To investigate the efficacy of the small-molecule MLK3 inhibitor URMC099 in reversing diet-induced murine NASH.
- To assess URMC099's impact on liver inflammation, injury, and fibrosis in a preclinical model.
Main Methods:
- C57BL/6J mice were fed a high-fat, high-fructose, high-cholesterol (FFC) diet or a chow diet for 24 weeks.
- Mice received intraperitoneal injections of URMC099 (10 mg/kg) or vehicle twice daily during the final 2 weeks.
- Evaluated parameters included body weight, caloric intake, insulin resistance, hepatic steatosis, macrophage activity, liver injury, and fibrosis.
Main Results:
- URMC099 treatment did not alter body weight, caloric intake, or insulin resistance in FFC-fed mice.
- URMC099 significantly reduced hepatic macrophage infiltration, activation, and pro-inflammatory polarization.
- FFC-fed mice treated with URMC099 exhibited decreased liver injury and fibrosis compared to vehicle controls.
Conclusions:
- URMC099 is well-tolerated in mice, showing no apparent toxicity.
- URMC099 demonstrates efficacy in reversing established diet-induced NASH in a murine model.
- URMC099 holds promise as a potential therapeutic agent for human NASH.
