4.5 Article

Flavin Adenine Dinucleotide Depletion Caused by electron transfer flavoprotein subunit alfa Haploinsufficiency Leads to Hepatic Steatosis and Injury in Zebrafish

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HEPATOLOGY COMMUNICATIONS
卷 5, 期 6, 页码 976-991

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JOHN WILEY & SONS LTD
DOI: 10.1002/hep4.1691

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资金

  1. Cell and Molecular Imaging Shared Resource, Medical University of South Carolina (MUSC) Cancer Center [P30 CA138313]
  2. South Carolina Center of Biomedical Research Excellence (SC COBRE) in Oxidants, Redox Balance, and Stress Signaling [P20 GM103542]
  3. SC COBRE in Digestive and Liver Diseases [P20 GM130457]
  4. MUSC Digestive Disease Core Center [P30 DK123704]
  5. MUSC Shared Instrumentation [S10 OD028663]

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This study reveals that ETFA haploinsufficiency leads to hyperlipidemia, hypercholesterolemia, hepatic steatosis, and injury in adult zebrafish. Reduction in levels of FAD and glutathione, as well as an increase in reactive oxygen species, was observed in mutant livers. Riboflavin supplementation counteracted these effects, highlighting the role of FAD depletion in hepatic steatosis and oxidative stress-mediated liver injury.
The electron transfer flavoprotein (ETF) complex, made up of the ETF alpha subunit (ETFA), ETF beta subunit (ETFB), and ETF dehydrogenase (ETFDH), regulates fatty acid beta-oxidation activity while scavenging leaked electrons through flavin adenine dinucleotide (FAD)/reduced form FAD (FADH(2)) redox reactions in mitochondria. Here, we hypothesized that ETF dysfunction-mediated FAD deficiency may result in increased mitochondrial oxidative stress and steatosis and subsequent liver injury. We report that etfa haploinsufficiency caused hyperlipidemia, hypercholesterolemia, and hepatic steatosis and injury in adult zebrafish. Further, etfa(+/)(-) mutant livers had reduced levels of FAD and glutathione and an increase in reactive oxygen species. Because FAD depletion might be critical in the pathogenesis of the liver lesion identified in etfa(+/)(-) mutants, we used riboflavin to elevate FAD levels in the liver and found that riboflavin supplementation significantly suppressed hepatic steatosis and injury in etfa(+/)(-) mutants through suppression of oxidative stress and de novo lipogenesis in the liver. Additionally, we found that adenosine triphosphate-linked mitochondrial oxygen consumption and mitochondrial membrane potential were reduced in etfa(+/)(-) primary hepatocytes and that riboflavin supplementation corrected these defects. Conclusion: FAD depletion caused by etfa haploinsufficiency plays a key role in hepatic steatosis and oxidative stress-mediated hepatic injury in adult zebrafish. This raises the possibility that people with ETFA haploinsufficiency have a high risk for developing liver disease.

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