title: Induction of a hypermetabolic state in cultured hepatocytes by glucagon and H2O2.
abstract: Stress hormones and pro-inflammatory cytokines are putative signals triggering increased energy expenditure or "hypermetabolism" commonly observed in inflammatory states. Cytokines also cause the release of reactive oxidants by immune cells resident in tissues in vivo. Therefore, we hypothesized that oxidative stress plays a role in the induction of hypermetabolism. We examined the effect of glucagon (1.0 nM), a catabolic stress hormone, and the oxidant H(2)O(2) (1.0 mM) on the metabolism of stable hepatocyte cultures for 4 days. Combined H(2)O(2) and glucagon treatment, but not H(2)O(2) or glucagon used alone, increased the hepatocyte oxygen uptake rate 25% above control untreated cells after a lag-time of 72 h. The same treatment also increased the expression of mitochondrial uncoupling protein-2 (UCP2). These effects were significantly inhibited by the antioxidant N-acetylcysteine (5mM) and the pentose phosphate pathway (PPP) inhibitor dehydroepianderosterone (200 microM). Glucagon alone induced urea synthesis and H(2)O(2) alone induced the PPP. These findings show, for the first time, that oxidative stress, in combination with glucagon, increases metabolic energy expenditure in cultured cells, and that this effect may be mediated by UCP-2. Furthermore, the results implicate the PPP in the induction of the hypermetabolic response.
authors.affiliation: Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kyongbum
authors.initials: K
authors.lastname: Lee
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Stephanopoulos
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007473:Ion Channels; D026901:Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D000071246:Uncoupling Protein 2
chemical_list: D004338:Drug Combinations; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D005934:Glucagon; D006861:Hydrogen Peroxide