Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis
Por:
Massey, V, Parrish, A, Argemi, J, Moreno, M, Mello, A, Garcia-Rocha, M, Altamirano, J, Odena, G, Dubuquoy, L, Louvet, A, Martinez, C, Adrover, A, Affo, S, Morales-Ibanez, O, Sancho-Bru, P, Millan, C, Alvarado-Tapias, E, Morales-Arraez, D, Caballeria, J, Mann, J, Cao, S, Sun, ZL, Shah, V, Cameron, A, Mathurin, P, Snider, N, Villanueva, C, Morgan, TR, Guinovart, J, Vadigepalli, R, Bataller, R
Publicada:
1 mar 2021
Ahead of Print:
1 abr 2021
Resumen:
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.
Filiaciones:
Massey, V:
Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27515 USA
Parrish, A:
Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Daniel Baugh Inst, Philadelphia, PA 19107 USA
Argemi, J:
Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA
Clin Univ Navarra, Liver Unit, Pamplona, Spain
IdisNA, Ctr Appl Med Res, Hepatol Program, Pamplona, Spain
Moreno, M:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Mello, A:
Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA
Garcia-Rocha, M:
Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain
Altamirano, J:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Internal Med Dept, Liver Unit, Barcelona, Spain
Odena, G:
Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27515 USA
Dubuquoy, L:
Univ Lille, Inserm LIRIC UMR995, CHU Lille, Serv Malad Appareil Digestif, Lille, France
Louvet, A:
Univ Lille, Inserm LIRIC UMR995, CHU Lille, Serv Malad Appareil Digestif, Lille, France
Martinez, C:
Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain
Adrover, A:
Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain
Affo, S:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Morales-Ibanez, O:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Sancho-Bru, P:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Millan, C:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Alvarado-Tapias, E:
Hosp Santa Creu & Sant Pau, Dept Gastroenterol, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Morales-Arraez, D:
Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA
Caballeria, J:
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Fac Med, CIBER Enfermedades Hepat & Digest, Hosp Clin,Liver Unit, Barcelona, Spain
Mann, J:
Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Fibrosis Res Grp, Newcastle Upon Tyne, Tyne & Wear, England
Cao, S:
Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA
Sun, ZL:
Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA
Johns Hopkins Sch Med, Transplant Biol Res Ctr, Baltimore, MD USA
Shah, V:
Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA
Cameron, A:
Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA
Johns Hopkins Sch Med, Transplant Biol Res Ctr, Baltimore, MD USA
Mathurin, P:
Univ Lille, Inserm LIRIC UMR995, CHU Lille, Serv Malad Appareil Digestif, Lille, France
Snider, N:
Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27515 USA
Villanueva, C:
Hosp Santa Creu & Sant Pau, Dept Gastroenterol, Barcelona, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
Hosp Santa Creu & Sant Pau, Inst Recerca, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Cerdanyola Del, Spain
Morgan, TR:
VA Long Beach Healthcare Syst, VA Long Beach Healthcare, Gastroenterol Serv, Long Beach, CA USA
Guinovart, J:
Barcelona Inst Sci & Technol, Inst Res Biomed, Barcelona, Spain
Vadigepalli, R:
Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Daniel Baugh Inst, Philadelphia, PA 19107 USA
Bataller, R:
Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27515 USA
Univ Pittsburgh, Med Ctr, Div Med, Dept Gastroenterol & Hepatol, Pittsburgh, PA USA
Green Accepted
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