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    Alcoholic liver disease (ALD) is closely linked to oxidative stress induction. Antioxidant enzymes balance oxidative stress and function as intermediary signaling regulators. Nucleoredoxin (NXN), an antioxidant enzyme, regulates physiological processes through redox-sensitive interactions. NXN interacts with myeloid differentiation primary response gene-88 (MYD88) and flightless-I (FLII) to regulate toll-like receptor 4 (TLR4)/MYD88 pathway activation, but FLII also regulates key cell processes and is secreted into the bloodstream. However, the effects of chronic ethanol consumption recapitulated by either ethanol alone or in combination with lipopolysaccharides (LPS), as a two-hit ALD model, on FLII/NXN/MYD88 complex and FLII secretion have not been explored yet. In this study, we have demonstrated that ethanol feeding increased FLII protein levels, its nuclear translocation and plasma secretion, and modified its tissue distribution both in vivo and in vitro ALD models. Ethanol increased MYD88/FLII interaction ratio, and decreased NXN/MYD88 interaction ratio but this was partially reverted by two-hit model. While ethanol and two-hit model increased MYD88/TLR4 interaction ratio, two-hit model significantly decreased FLII nuclear translocation and its plasma secretion. Ethanol and LPS provoked similar effects in vitro; however, NXN overexpression partially reverted these alterations, and ethanol alone increased FLII secretion into culture medium. In summary, by analyzing the response of FLII/NXN/MYD88 complex during ALD early progression both in vivo and in vitro, we have discovered that the effects of chronic ethanol consumption disrupt this complex and identified FLII as a candidate non-invasive plasma biomarker for the early detection of ALD. Copyright © 2020. Published by Elsevier Inc.

    Citation

    Jaime Arellanes-Robledo, Joseph Ibrahim, Karina Reyes-Gordillo, Ruchi Shah, Leslie Leckey, M Raj Lakshman. Flightless-I is a potential biomarker for the early detection of alcoholic liver disease. Biochemical pharmacology. 2021 Jan;183:114323

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    PMID: 33166508

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