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Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission and mitophagy.

Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission and mitophagy.
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Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J,


Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J, (click to view)

Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J,

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Journal of pineal research 2017 10 05() doi 10.1111/jpi.12450
Abstract

Mitochondrial dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through poorly defined mechanisms. Melatonin supplementation has been found to protect liver function in diabetes and obesity. Here, we intensively explored the role and mechanism of melatonin in the development of NAFLD. We demonstrated that the onset of diet-induced NAFLD greatly caused NR4A1 upregulation in hepatocytes, leading to the activation of DNA-PKcs and p53. On the one hand, p53 aided Drp1 migration in the mitochondria and consequently drove mitochondrial fission. On the other hand, p53 repressed Bnip3 transcription and expression, resulting into mitophagy arrest. The excessive fission and deficient mitophagy dramatically mediated mitochondrial dysfunction, including extensive mPTP opening, reduction in mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse and ATP shortage. However, genetic deletion of NR4A1 or DNA-PKcs could definitively reverse NAFLD progression and the mitochondrial dysfunction. Similarly, melatonin supplementation could robustly reduce the damage to liver and mitochondrial structure and function in NAFLD. Mechanistically, melatonin halted fission but recovered mitophagy via blockade of NR4A1/DNA-PKcs/p53 pathway, finally improving mitochondrial and liver function in the setting of NAFLD. Our results identify NR4A1/DNA-PKcs/p53 pathway as the novel molecular mechanism underlying the pathogenesis of NAFLD via regulation Drp1-mediated mitochondrial fission and Bnip3-related mitophagy. Meanwhile, we also confirm that melatonin has the ability to cut off the NR4A1/DNA-PKcs/p53 pathway, which confers a protective advantage to hepatocytes and mitochondria. The manipulation of NR4A1/DNA-PKcs/p53 pathway by melatonin highlights a new entry point for treating NAFLD. This article is protected by copyright. All rights reserved.

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