1. Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis
- Author
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Massey, Veronica, Parrish, Austin, Argemi, Josepmaria, Moreno, Montserrat, Mello, Aline, García-Rocha, Mar, Altamirano, Jose, Odena, Gemma, Dubuquoy, Laurent, Louvet, Alexandre, Martinez, Carlos, Adrover, Anna, Affò, Silvia, Morales-Ibanez, Oriol, Sancho-Bru, Pau, Millán, Cristina, Alvarado-Tapias, Edilmar, Morales-Arraez, Dalia, Caballería, Juan, Mann, Jelena, Cao, Sheng, Sun, Zhaoli, Shah, Vijay, Cameron, Andrew, Mathurin, Phillipe, Snider, Natasha, Villanueva, Càndid, Morgan, Timothy R, Guinovart, Joan, Vadigepalli, Rajanikanth, and Bataller, Ramon
- Subjects
Medical Biochemistry and Metabolomics ,Biomedical and Clinical Sciences ,Clinical Sciences ,Liver Disease ,Hepatitis ,Chronic Liver Disease and Cirrhosis ,Alcoholism ,Alcohol Use and Health ,Substance Misuse ,Nutrition ,Digestive Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Acute Kidney Injury ,Adaptation ,Physiological ,Animals ,Cell Dedifferentiation ,Energy Metabolism ,Europe ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Enzymologic ,Glucose ,Glucose-6-Phosphate ,Glycogen ,Hep G2 Cells ,Hepatitis ,Alcoholic ,Hepatocytes ,Hexokinase ,Humans ,Liver ,Male ,Metabolome ,Metabolomics ,Middle Aged ,Rats ,Wistar ,Transcriptome ,United States ,Alcoholic Liver Disease ,Therapeutic Targets ,Neurosciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
Background & aimsWe 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.MethodsWe 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.ResultsPatients 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.ConclusionsAltered 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.
- Published
- 2021