Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 in 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 of 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.
 ...
PMID:Effects of melatonin on fatty liver disease: The role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. 2898 Nov 57

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcs LKO ) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.
 ...
PMID:DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. 3183 99

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.
 ...
PMID:DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. 3327 70