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Transition between acute and chronic hepatotoxicity in mice is associated with impaired energy metabolism and induction of mitochondrial heme oxygenase-1.

Nikam A, Patankar JV, Lackner C, Schöck E, Kratky D, Zatloukal K, Abuja PM - PLoS ONE (2013)

Bottom Line: The formation of protein inclusions is frequently associated with chronic metabolic diseases.To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks.At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.

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.

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Oxidative damage to liver tissue during DDC-intoxication.MDA-protein adduct levels (pmol/mg protein) in (A) liver homogenate and (B) mitochondria. Concentrations of 8-OHdG (ng/µg DNA) in (C) liver homogenate, representing total DNA, and (D) mitochondria. Data are mean ± SD from 5 mice per treatment group. Significant differences were found compared to controls (*** p<0.001), but not between treatment groups.
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pone-0066094-g003: Oxidative damage to liver tissue during DDC-intoxication.MDA-protein adduct levels (pmol/mg protein) in (A) liver homogenate and (B) mitochondria. Concentrations of 8-OHdG (ng/µg DNA) in (C) liver homogenate, representing total DNA, and (D) mitochondria. Data are mean ± SD from 5 mice per treatment group. Significant differences were found compared to controls (*** p<0.001), but not between treatment groups.

Mentions: Oxidative liver damage was assessed as MDA-protein adducts, corresponding to lipid peroxidation, and 8-OHdG (DNA damage), both in whole-liver homogenate, and in mitochondrial preparations (Fig. 3). In homogenate, MDA-protein reached near-maximal levels (about 2-fold increased) already after 1 week (Fig. 3A). In mitochondria (Fig. 3B) we found a 2.5-fold increase during the first 2 weeks, subsequently increasing to 4-fold concentration compared to controls. 8-OHdG in homogenate, representing a mixture of damage to nuclear and mitochondrial DNA (mtDNA), increased 2.5-fold after 5 weeks and 4-fold thereafter (Fig. 3C). 8-OHdG in mtDNA alone increased almost 2-fold already after one week, subsequently remaining at this level (Fig. 3D). Taken together, lipid peroxidation at late stages of DDC-intoxication was most pronounced in mitochondria while DNA damage increased predominantly in the nucleus.


Transition between acute and chronic hepatotoxicity in mice is associated with impaired energy metabolism and induction of mitochondrial heme oxygenase-1.

Nikam A, Patankar JV, Lackner C, Schöck E, Kratky D, Zatloukal K, Abuja PM - PLoS ONE (2013)

Oxidative damage to liver tissue during DDC-intoxication.MDA-protein adduct levels (pmol/mg protein) in (A) liver homogenate and (B) mitochondria. Concentrations of 8-OHdG (ng/µg DNA) in (C) liver homogenate, representing total DNA, and (D) mitochondria. Data are mean ± SD from 5 mice per treatment group. Significant differences were found compared to controls (*** p<0.001), but not between treatment groups.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675145&req=5

pone-0066094-g003: Oxidative damage to liver tissue during DDC-intoxication.MDA-protein adduct levels (pmol/mg protein) in (A) liver homogenate and (B) mitochondria. Concentrations of 8-OHdG (ng/µg DNA) in (C) liver homogenate, representing total DNA, and (D) mitochondria. Data are mean ± SD from 5 mice per treatment group. Significant differences were found compared to controls (*** p<0.001), but not between treatment groups.
Mentions: Oxidative liver damage was assessed as MDA-protein adducts, corresponding to lipid peroxidation, and 8-OHdG (DNA damage), both in whole-liver homogenate, and in mitochondrial preparations (Fig. 3). In homogenate, MDA-protein reached near-maximal levels (about 2-fold increased) already after 1 week (Fig. 3A). In mitochondria (Fig. 3B) we found a 2.5-fold increase during the first 2 weeks, subsequently increasing to 4-fold concentration compared to controls. 8-OHdG in homogenate, representing a mixture of damage to nuclear and mitochondrial DNA (mtDNA), increased 2.5-fold after 5 weeks and 4-fold thereafter (Fig. 3C). 8-OHdG in mtDNA alone increased almost 2-fold already after one week, subsequently remaining at this level (Fig. 3D). Taken together, lipid peroxidation at late stages of DDC-intoxication was most pronounced in mitochondria while DNA damage increased predominantly in the nucleus.

Bottom Line: The formation of protein inclusions is frequently associated with chronic metabolic diseases.To evaluate the mechanistic underpinnings for this dichotomy we dissected the time-course of DDC intoxication for up to 10 weeks.At this transition stage, adaptive responses involving mtHO-1 were induced, indirectly leading to improved respiration and preventing further drop of ATP levels.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.

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.

Show MeSH
Related in: MedlinePlus