TY - JOUR
T1 - Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis
AU - Massey, Veronica
AU - Parrish, Austin
AU - Argemi, Josepmaria
AU - Moreno, Montserrat
AU - Mello, Aline
AU - García-Rocha, Mar
AU - Altamirano, Jose
AU - Odena, Gemma
AU - Dubuquoy, Laurent
AU - Louvet, Alexandre
AU - Martinez, Carlos
AU - Adrover, Anna
AU - Affò, Silvia
AU - Morales-Ibanez, Oriol
AU - Sancho-Bru, Pau
AU - Millán, Cristina
AU - Alvarado-Tapias, Edilmar
AU - Morales-Arraez, Dalia
AU - Caballería, Juan
AU - Mann, Jelena
AU - Cao, Sheng
AU - Sun, Zhaoli
AU - Shah, Vijay
AU - Cameron, Andrew
AU - Mathurin, Phillipe
AU - Snider, Natasha
AU - Villanueva, Càndid
AU - Morgan, Timothy R.
AU - Guinovart, Joan
AU - Vadigepalli, Rajanikanth
AU - Bataller, Ramon
N1 - Publisher Copyright:
© 2021
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - Alcoholic Liver Disease
KW - Metabolomics
KW - Therapeutic Targets
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UR - http://www.scopus.com/inward/citedby.url?scp=85102012004&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.12.008
DO - 10.1053/j.gastro.2020.12.008
M3 - Article
C2 - 33309778
AN - SCOPUS:85102012004
SN - 0016-5085
VL - 160
SP - 1725-1740.e2
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -