4.7 Article

A small-molecule JNK inhibitor JM-2 attenuates high-fat diet-induced non-alcoholic fatty liver disease in mice

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INTERNATIONAL IMMUNOPHARMACOLOGY
卷 115, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.intimp.2022.109587

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Non-alcoholic fatty liver disease; JNK; Pharmacological inhibitor; Inflammation; Hepatocyte

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A novel JNK inhibitor, JM-2, was found to have therapeutic effects against non-alcoholic fatty liver disease (NAFLD). In vitro, JM-2 suppressed JNK activation, inflammation, and cell apoptosis. In vivo, JM-2 protected mice from HFD-induced inflammation, lipid accumulation, fibrosis, and apoptosis.
Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has been deemed a leading cause of end-stage liver disease. As a member of the mitogen-activated protein kinase family, c-Jun N-terminal kinase (JNK) has been shown to play an important role in the pathogenesis of NAFLD. Here, we identified a novel JNK in-hibitor, JM-2, and evaluated its therapeutic effects against NAFLD both in vitro and in vivo.Methods: In vitro, JNK was blocked by JM-2 in PA-challenged hepatocytes. C57BL/6 mice were fed a high-fat diet for 6 months to develop NAFLD. Mice were treated with JM-2 by intragastric administration.Results: In primary hepatocytes and AML-12 cells, JM-2 treatment significantly suppressed palmitic acid (PA)-induced JNK activation and PA-induced inflammation and cell apoptosis. In addition, JM-2 restricted the pro-duction of fibrosis-and lipid metabolism-related genes in PA-challenged hepatocytes. We evaluated the curative effect of JM-2 against NAFLD using a high-fat diet (HFD)-fed mouse model. Based on our findings, JM-2 administration significantly protected the mouse liver from HFD-induced inflammation, lipid accumulation, fibrosis, and apoptosis, accompanied with reduced JNK phosphorylation in the liver tissue.Conclusion: JM-2 affords a significant protective effect against HFD-induced NAFLD by inhibiting JNK activation and is potential to be developed as a candidate drug for NAFLD treatment.

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