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Hepatology
Original article
Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression
  1. Mi Jeong Heo1,
  2. Tae Hyun Kim1,
  3. Jueng Soo You2,
  4. Delia Blaya3,
  5. Pau Sancho-Bru3,
  6. Sang Geon Kim1
  1. 1 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
  2. 2 Department of Biochemistry, School of Medicine, Konkuk University, Seoul, Republic of Korea
  3. 3 Laboratory of Liver Cell Plasticity and Tissue Repair, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas (CIBERehd), Barcelona, Spain
  1. Correspondence to Dr. Sang Geon Kim, College of Pharmacy, Seoul National University, 1Gwanakro, Seoul 08826, Republic of Korea; sgk{at}snu.ac.kr

Abstract

Objective Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis.

Design Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models.

Results The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for MIR148A transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small-interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury.

Conclusion Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.

  • alcohol-induced injury
  • inflammation
  • cell death
  • cell signalling

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-315123

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    Footnotes

    • Contributors MJH: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; statistical analysis. THK: study concept and design; acquisition of data; analysis and interpretation of data. JSY study concept and design; acquisition of data; analysis and interpretation of data; administrative, technical or material support. DB: acquisition of data; analysis and interpretation of data; statistical analysis. PS-B: study concept and design; human sample analysis and interpretation of data; administrative, technical or material support. SGK: study concept and design; analysis and interpretation of data; writing of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; administrative, technical or material support and study supervision.

    • Funding This research was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (NRF-2015R1A2A1A10052663) and MJH was supported by Basic Science Research Program of the Ministry of Education (NRF-2018R1A6A3A01011724). Sancho-Bru P was supported by Instituto de Salud Carlos III, Miguel Servet CP11/00071 and FIS PI14/00320 and cofinanced by Fondo Europeo de Desarrollo Europeo (FEDER), Unión Europea, ’Una manera de hacer Europa'.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Ethics Committees of Seoul National University and the Hospital Clinic of Barcelona.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it published Online First. The funding statement has been updated.

    • Presented at A part of the data included in this manuscript was presented at the 2017 Spring International Convention of the Pharmaceutical Society of Korea in Korea (2017).