Title :

Integrated multi-omics reveals glucose use reprogramming and identifies a novel hexokinase in alcoholic hepatitis

Author(s) :

Massey, Veronica [Auteur]
University of North Carolina [Chapel Hill] [UNC]
Parrish, Austin [Auteur]
Argemi, Josepmaria [Auteur]
University of Pittsburgh [PITT]
Moreno, Montserrat [Auteur]
University of Barcelona
Mello, Aline [Auteur]
University of Pittsburgh [PITT]
Garcia-Rocha, Mar [Auteur]
Barcelona Institute of Science and Technology [BIST]
Altamirano, Jose [Auteur]
University of Barcelona
Vall d'Hebron University Hospital [Barcelona]
Odena, Gemma [Auteur]
University of North Carolina [Chapel Hill] [UNC]
Dubuquoy, Laurent [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Louvet, Alexandre [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Martinez, Carlos [Auteur]
Barcelona Institute of Science and Technology [BIST]
Adrover, Anna [Auteur]
Barcelona Institute of Science and Technology [BIST]
Affo, Silvia [Auteur]
University of Barcelona
Morales-Ibanez, Oriol [Auteur]
University of Barcelona
Sancho-Bru, Pau [Auteur]
University of Barcelona
Millan, Cristina [Auteur]
University of Barcelona
Alvarado-Tapias, Edilmar [Auteur]
University of Barcelona
Instituto de Salud Carlos III [Madrid] [ISCIII]
Morales-Arraez, Dalia [Auteur]
University of Pittsburgh [PITT]
Caballeria, Juan [Auteur]
University of Barcelona
Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas [CIBERehd]
Mann, Jelena [Auteur]
Newcastle University [Newcastle]
Cao, Sheng [Auteur]
Mayo Clinic [Rochester]
Sun, Zhaoli [Auteur]
Johns Hopkins University School of Medicine [Baltimore]
Shah, Vijay H. [Auteur]
Mayo Clinic [Rochester]
Cameron, Andrew [Auteur]
Johns Hopkins University School of Medicine [Baltimore]
Mathurin, Philippe [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Snider, Natasha [Auteur]
University of North Carolina [Chapel Hill] [UNC]
Villanueva, Candid [Auteur]
University of Barcelona
Instituto de Salud Carlos III [Madrid] [ISCIII]
Morgan, Timothy R. [Auteur]
California State University [Long Beach] [CSULB ]
Guinovart, Joan [Auteur]
Institute for Research in Biomedicine [Barcelona, Spain] [IRB]
Vadigepalli, Rajanikanth [Auteur]
Jefferson University Hospitals
Bataller, Ramon [Auteur]
University of Pittsburgh [PITT]
University of North Carolina [Chapel Hill] [UNC]

Journal title :

Gastroenterology

Abbreviated title :

Gastroenterology

Publication date :

2020-12-09

ISSN :

1528-0012

Keyword(s) :

Alcoholic Liver Disease
Metabolomics
Therapeutic Targets

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

OBJECTIVE: 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 ...
Show more >OBJECTIVE: 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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Submission date :

2021-07-06T12:50:26Z
2024-01-30T13:09:59Z