Veronica Massey1, Austin Parrish2, Josepmaria Argemi3, Montserrat Moreno4, Aline Mello5, Mar García-Rocha6, Jose Altamirano7, Gemma Odena1, Laurent Dubuquoy8, Alexandre Louvet8, Carlos Martinez6, Anna Adrover6, Silvia Affò4, Oriol Morales-Ibanez4, Pau Sancho-Bru4, Cristina Millán4, Edilmar Alvarado-Tapias9, Dalia Morales-Arraez5, Juan Caballería10, Jelena Mann11, Sheng Cao12, Zhaoli Sun13, Vijay Shah12, Andrew Cameron13, Phillipe Mathurin8, Natasha Snider14, Càndid Villanueva15, Timothy R Morgan16, Joan Guinovart6, Rajanikanth Vadigepalli2, Ramon Bataller17. 1. Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, North Carolina. 2. Daniel Baugh Institute, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. 3. Department of Gastroenterology and Hepatology, Division of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Liver Unit, Clinica Universidad de Navarra. Hepatology Program, Center for Applied Medical Research, IdisNA, Pamplona, Spain. 4. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 5. Department of Gastroenterology and Hepatology, Division of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 6. Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Barcelona, Spain. 7. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebrón, Vall d'Hebrón Institut de Recerca, Barcelona, Spain. 8. Service des Maladies de l'appareil digestif, CHU Lille, Inserm LIRIC-UMR995, University of Lille, Lille, France. 9. Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain. 10. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Liver Unit, Hospital Clínic, CIBER de Enfermedades Hepáticas y Digestivas, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. 11. Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom. 12. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 13. Johns Hopkins School of Medicine, Department of Surgery and Transplant Biology Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland. 14. Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina. 15. Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain. 16. Gastroenterology Services, VA Long Beach Healthcare, VA Long Beach Healthcare System, Long Beach, California. 17. Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, North Carolina; Department of Gastroenterology and Hepatology, Division of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: bataller@pitt.edu.
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.
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.
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