Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis.
Acute Kidney Injury
/ enzymology
Adaptation, Physiological
Animals
Cell Dedifferentiation
Energy Metabolism
Europe
Female
Gene Expression Profiling
Gene Expression Regulation, Enzymologic
Glucose
/ metabolism
Glucose-6-Phosphate
/ metabolism
Glycogen
/ metabolism
Hep G2 Cells
Hepatitis, Alcoholic
/ enzymology
Hepatocytes
/ enzymology
Hexokinase
/ genetics
Humans
Liver
/ enzymology
Male
Metabolome
Metabolomics
Middle Aged
Rats, Wistar
Transcriptome
United States
Alcoholic Liver Disease
Metabolomics
Therapeutic Targets
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
23
02
2020
revised:
06
11
2020
accepted:
01
12
2020
pubmed:
15
12
2020
medline:
31
8
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33309778
pii: S0016-5085(20)35542-6
doi: 10.1053/j.gastro.2020.12.008
pmc: PMC8613537
mid: NIHMS1754432
pii:
doi:
Substances chimiques
Glucose-6-Phosphate
56-73-5
Glycogen
9005-79-2
HKDC1 protein, human
EC 2.7.1.1
Hexokinase
EC 2.7.1.1
Hkdc1 protein, rat
EC 2.7.1.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1725-1740.e2Subventions
Organisme : NIAAA NIH HHS
ID : U01 AA026264
Pays : United States
Organisme : Medical Research Council
ID : MR/R023026/1
Pays : United Kingdom
Organisme : NIAAA NIH HHS
ID : R01 AA018873
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA027054
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026978
Pays : United States
Organisme : NIAAA NIH HHS
ID : F31 AA024969
Pays : United States
Organisme : NIAAA NIH HHS
ID : T32 AA007463
Pays : United States
Organisme : NIAAA NIH HHS
ID : R24 AA025017
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA021908
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110355
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026972
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
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