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Moreno MAuthorAltamirano JAuthorAffo SAuthorMorales-Ibanez OAuthorSancho-Bru PAuthorMillan CAuthorCaballeria JAuthorBataller, RCorresponding Author

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January 3, 2021
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INTEGRATED MULTI-OMICS REVEALS GLUCOSE USE REPROGRAMMING AND IDENTIFIES A NOVEL HEXOKINASE IN ALCOHOLIC HEPATITIS

Publicated to: Gastroenterology. 160 (5): 1725-+ - 2021-04-06 160(5), DOI: 10.1053/j.gastro.2020.12.008

Authors:

Massey, Veronica; Parrish, Austin; Argemi, Josepmaria; Moreno, Montserrat; Mello, Aline; Garcia-Rocha, Mar; Altamirano, Jose; Odena, Gemma; Dubuquoy, Laurent; Louvet, Alexandre; Martinez, Carlos; Adrover, Anna; Affo, Silvia; Morales-Ibanez, Oriol; Sancho-Bru, Pau; Millan, Cristina; Alvarado-Tapias, Edilmar; Morales-Arraez, Dalia; Caballeria, Juan; Mann, Jelena; Cao, Sheng; Sun, Zhaoli; Shah, Vijay; Cameron, Andrew; Mathurin, Phillipe; Snider, Natasha; Villanueva, Candid; Morgan, Timothy R; Morgan, Timothy R; Guinovart, Joan; Vadigepalli, Rajanikanth; Bataller, Ramon
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Affiliations

Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain - Author
Clin Univ Navarra, Liver Unit, Pamplona, Spain - Author
Hosp Santa Creu & Sant Pau, Dept Gastroenterol, Barcelona, Spain - Author
Hosp Santa Creu & Sant Pau, Inst Recerca, Barcelona, Spain - Author
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Internal Med Dept, Liver Unit, Barcelona, Spain - Author
IdisNA, Ctr Appl Med Res, Hepatol Program, Pamplona, Spain - Author
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain - Author
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain - Author
Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA - Author
Johns Hopkins Sch Med, Transplant Biol Res Ctr, Baltimore, MD USA - Author
Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA - Author
Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Fibrosis Res Grp, Newcastle Upon Tyne, Tyne & Wear, England - Author
Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Daniel Baugh Inst, Philadelphia, PA 19107 USA - Author
Univ Autonoma Barcelona, Barcelona, Cerdanyola Del, Spain - Author
Univ Barcelona, Fac Med, CIBER Enfermedades Hepat & Digest, Hosp Clin,Liver Unit, Barcelona, Spain - Author
Univ Lille, Inserm LIRIC UMR995, CHU Lille, Serv Malad Appareil Digestif, Lille, France - Author
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27515 USA - Author
Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27515 USA - Author
Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA - Author
Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA - Author
Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA - Author
VA Long Beach Healthcare Syst, VA Long Beach Healthcare, Gastroenterol Serv, Long Beach, CA USA - Author
‎ Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain - Author
‎ Clin Univ Navarra, Liver Unit, Pamplona, Spain - Author
‎ Hosp Santa Creu & Sant Pau, Dept Gastroenterol, Barcelona, Spain - Author
‎ Hosp Santa Creu & Sant Pau, Inst Recerca, Barcelona, Spain - Author
‎ Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Internal Med Dept, Liver Unit, Barcelona, Spain - Author
‎ IdisNA, Ctr Appl Med Res, Hepatol Program, Pamplona, Spain - Author
‎ Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain - Author
‎ Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain - Author
‎ Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA - Author
‎ Johns Hopkins Sch Med, Transplant Biol Res Ctr, Baltimore, MD USA - Author
‎ Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA - Author
‎ Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Fibrosis Res Grp, Newcastle Upon Tyne, Tyne & Wear, England - Author
‎ Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Daniel Baugh Inst, Philadelphia, PA 19107 USA - Author
‎ Univ Autonoma Barcelona, Barcelona, Cerdanyola Del, Spain - Author
‎ Univ Barcelona, Fac Med, CIBER Enfermedades Hepat & Digest, Hosp Clin,Liver Unit, Barcelona, Spain - Author
‎ Univ Lille, Inserm LIRIC UMR995, CHU Lille, Serv Malad Appareil Digestif, Lille, France - Author
‎ Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27515 USA - Author
‎ Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27515 USA - Author
‎ Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA - Author
‎ Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA - Author
‎ Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA - Author
‎ VA Long Beach Healthcare Syst, VA Long Beach Healthcare, Gastroenterol Serv, Long Beach, CA USA - Author
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Abstract

We recently demonstrated that alcoholic hepatitis (AH) is characterized by de-differentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism.We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH, alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing (ChIP-seq) was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells.Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome revealed the utilization of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in AH patients. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in AH patients. Histone active promoter and enhancer markers were increased in HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes.Altered metabolite levels and mRNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Keywords

expressiongenehkdc1metabolismmetabolomicspentoxifyllineprednisolonetherapeutic targetsAcute kidney failureAcute kidney injuryAdaptation, physiologicalAdultAlcohol liver diseaseAlcoholic liver diseaseAnimal cellAnimalsArticleCell dedifferentiationChromatin immunoprecipitationCitric acid cycleClinical articleClinical trialCohort analysisControlled studyDisaccharideDna sequencingDown regulationEnergy metabolismEnhancer regionEnzymologyEuropeExpressionFemaleGeneGene expressionGene expression profilingGene expression regulationGene expression regulation, enzymologicGenetic markerGeneticsGluconeogenesisGlucoseGlucose 6 phosphateGlucose metabolismGlucose-6-phosphateGlycogenGlycolysisHep g2 cellsHep-g2 cell lineHepatitis, alcoholicHepatocytesHexokinaseHexokinase 1Hkdc1Hkdc1 protein, humanHkdc1 protein, ratHumanHuman cellHuman tissueHumansIn vitro studyLiverLiver cellLiver resectionLiver tissueMaleMetabolismMetabolomeMetabolomicsMiddle agedMonosaccharideMulticenter studyPathologyPentoxifyllinePrednisoloneRatsRats, wistarTherapeutic targetsTranscriptomeUnited statesWistar rat

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal GASTROENTEROLOGY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 3/93, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.77. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 13, 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2026-04-02, the following number of citations:

  • WoS: 58
  • Scopus: 2
  • Europe PMC: 51
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 42.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 42 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 3.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France; Timor-Leste; United Kingdom; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (Bataller Alberola, Ramon).

the author responsible for correspondence tasks has been Bataller Alberola, Ramon.

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Awards linked to the item

Jose Altamirano was partially supported by the Mexican National Council of Science and Technology (Mexico City, Mexico) for his predoctoral stay in Barcelona, Spain. Paul Sancho-Bru was supported by grants from Fondo de Investigacion Sanitaria Carlos III, cofinanced by Fondo Europeo de Desarrollo Regional, Union Europea, Una manera de hacer Europa PI17/00673 and PI20/00765, and Miguel Servet, CPII16/0004. Andrew Cameron was supported by National Institutes of Health (NIH)/National Institute on Alcohol Abuse and Alcoholism (NIAAA) (grant P50AA027054). Zhaoli Sun was supported by the NIH/NIAAA (grant R24 AA025017). Joan Guinovart was supported by grants from the Spanish MINECO (BFU2017-84345-P) and the CIBER de Diabetes y Enfermedades Metabolicas. Ramon Bataller is supported by the NIH/NIAAA (grants AA026972, AA026978, and AA026264) and National Institute of Diabetes and Digestive and Kidney Diseases (grant P30DK120531).
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