Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis

Veronica Massey, Austin Parrish, Josepmaria Argemi, Montserrat Moreno, Aline Mello, Mar García-Rocha, Jose Altamirano, Gemma Odena, Laurent Dubuquoy, Alexandre Louvet, Carlos Martinez, Anna Adrover, Silvia Affò, Oriol Morales-Ibanez, Pau Sancho-Bru, Cristina Millán, Edilmar Alvarado-Tapias, Dalia Morales-Arraez, Juan Caballería, Jelena MannSheng Cao, Zhaoli Sun, Vijay Shah, Andrew Cameron, Phillipe Mathurin, Natasha Snider, Càndid Villanueva, Timothy R. Morgan, Joan Guinovart, Rajanikanth Vadigepalli, Ramon Bataller

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background & Aims: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation 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. Methods: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. Results: 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 showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the 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. Conclusions: Altered metabolite levels and messenger RNA 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.

Original languageEnglish (US)
Pages (from-to)1725-1740.e2
JournalGastroenterology
Volume160
Issue number5
DOIs
StatePublished - Apr 2021

Keywords

  • Alcoholic Liver Disease
  • Metabolomics
  • Therapeutic Targets

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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