title: A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease.
abstract: OBJECTIVE
  The cause of hepatic failure in the terminal stages of chronic injury is unknown. Cellular metabolic adaptations in response to the microenvironment have been implicated in cellular breakdown.
  
  
  METHODS
  To address the role of energy metabolism in this process we studied mitochondrial number, respiration, and functional reserve, as well as cellular adenosine-5'-triphosphate (ATP) production, glycolytic flux, and expression of glycolysis related genes in isolated hepatocytes from early and terminal stages of cirrhosis using a model that produces hepatic failure from irreversible cirrhosis in rats. To study the clinical relevance of energy metabolism in terminal stages of chronic liver failure, we analyzed glycolysis and energy metabolism related gene expression in liver tissue from patients at different stages of chronic liver failure according to Child-Pugh classification. Additionally, to determine whether the expression of these genes in early-stage cirrhosis (Child-Pugh Class A) is related to patient outcome, we performed network analysis of publicly available microarray data obtained from biopsies of 216 patients with hepatitis C-related Child-Pugh A cirrhosis who were prospectively followed up for a median of 10years.
  
  
  RESULTS
  In the early phase of cirrhosis, mitochondrial function and ATP generation are maintained by increasing energy production from glycolytic flux as production from oxidative phosphorylation falls. At the terminal stage of hepatic injury, mitochondria respiration and ATP production are significantly compromised, as the hepatocytes are unable to sustain the increased demand for high levels of ATP generation from glycolysis. This impairment corresponds to a decrease in glucose-6-phosphatase catalytic subunit and phosphoglucomutase 1. Similar decreased gene expression was observed in liver tissue from patients at different stages of chronic liver injury. Further, unbiased network analysis of microarray data revealed that expression of these genes was down regulated in the group of patients with poor outcome.
  
  
  CONCLUSIONS
  An adaptive metabolic shift, from generating energy predominantly from oxidative phosphorylation to glycolysis, allows maintenance of energy homeostasis during early stages of liver injury, but leads to hepatocyte dysfunction during terminal stages of chronic liver disease because hepatocytes are unable to sustain high levels of energy production from glycolysis.
authors.affiliation: Center for Innovative Regenerative Therapies, Department of Surgery, Transplantation Section, Children's Hospital of Pittsburgh, USA; Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Damm
authors.affiliation: Center for Innovative Regenerative Therapies, Department of Surgery, Transplantation Section, Children's Hospital of Pittsburgh, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Bing
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Handa
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Mladen I
authors.initials: MI
authors.lastname: Yovchev
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sehgal
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Moss
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oertel
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Prahlad T
authors.initials: PT
authors.lastname: Ram
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Iraklis I
authors.initials: II
authors.lastname: Pipinos
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: sotogutierreza@upmc.edu.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.affiliation: Center for Innovative Regenerative Therapies, Department of Surgery, Transplantation Section, Children's Hospital of Pittsburgh, USA; McGowan Institute for Regenerative Medicine and Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: foxi@upmc.edu.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, TX, USA. Electronic address: deepak.nagrath@rice.edu.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010634:Phenobarbital / Q000633:toxicity; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D008565:Membrane Proteins; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D005947:Glucose; D010634:Phenobarbital
keywords: Acute-in-chronic liver failure; Adenosine-5′-triphosphate; Decompensated liver cirrhosis; Glycolysis; Hepatocytes; Mitochondria