title: Transition between acute and chronic hepatotoxicity in mice is associated with impaired energy metabolism and induction of mitochondrial heme oxygenase-1.
abstract: The formation of protein inclusions is frequently associated with chronic metabolic diseases. In mice, short-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) leads to hepatocellular damage indicated by elevated serum liver enzyme activities, whereas only minor morphological changes are observed. Conversely, chronic administration of DDC for several weeks results in severe morphological damage, characterized by hepatocellular ballooning, disruption of the intermediate filament cytoskeleton, and formation of Mallory-Denk bodies consisting predominantly of misfolded keratins, Sqstm1/p62, and heat shock proteins. To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks. We determined body weight change, serum liver enzyme activities, morphologic alterations, induction of antioxidant response (heme oxygenase-1, HO-1), oxidative damage and ATP content in livers as well as respiration, oxidative damage and the presence and activity of HO-1 in endoplasmic reticulum and mitochondria (mtHO-1). Elevated serum liver enzyme activity and oxidative liver damage were already present at early intoxication stages without further subsequent increase. After 2 weeks of intoxication, mice had transiently lost 9% of their body weight, liver ATP-content was reduced to 58% of controls, succinate-driven respiration was uncoupled from ATP-production and antioxidant response was associated with the appearance of catalytically active mtHO-1. Oxidative damage was associated with both acute and chronic DDC toxicity whereas the onset of chronic intoxication was specifically associated with mitochondrial dysfunction which was maximal after 2 weeks of intoxication. At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels. Our observations clearly demonstrate principally different mechanisms for acute and chronic toxic damage.
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Aniket
authors.initials: A
authors.lastname: Nikam
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schöck
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Peter M
authors.initials: PM
authors.lastname: Abuja
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D059609:Mallory Bodies / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017510:Protein Folding; D011725:Pyridines / Q000633:toxicity*; D000071456:Sequestosome-1 Protein; D013997:Time Factors
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D011725:Pyridines; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D007633:Keratins; D000255:Adenosine Triphosphate; D051547:Heme Oxygenase-1