Transition between Acute and Chronic Hepatotoxicity in Mice Is Associated with Impaired Energy Metabolism and Induction of Mitochondrial Heme Oxygenase-1

被引:15
|
作者
Nikam, Aniket [1 ]
Patankar, Jay V. [2 ]
Lackner, Carolin [1 ]
Schoeck, Elisabeth [1 ]
Kratky, Dagmar [2 ]
Zatloukal, Kurt [1 ]
Abuja, Peter M. [1 ]
机构
[1] Med Univ Graz, Inst Pathol, Graz, Austria
[2] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria
来源
PLOS ONE | 2013年 / 8卷 / 06期
基金
奥地利科学基金会;
关键词
NONALCOHOLIC STEATOHEPATITIS; HEPATIC FERROCHELATASE; RESPIRATORY-CHAIN; ENZYME-ACTIVITIES; ATP HOMEOSTASIS; MALLORY BODIES; LIVER; INHIBITION; DYSFUNCTION; MECHANISM;
D O I
10.1371/journal.pone.0066094
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:11
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