Limits...
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.

Show MeSH

Related in: MedlinePlus

Expression of Nrf2 and heme oxygenase 1 in livers of DDC-treated mice.A: Nrf2 protein expression and (B) densitometry in hepatic nuclear fractions. The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (Lamin A/C) C: Heme oxygenase-1 (HO-1) protein expression and (D) densitometry in total liver homogenate (HO-1) and mitochondrial fractions (mtHO-1). The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (calnexin for total homogenate, Ponceau S for the mitochondrial fraction). (E) Activities of HO-1 in microsomes and mtHO-1 in mitochondria as pmol bilirubin/mg protein/h.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3675145&req=5

pone-0066094-g005: Expression of Nrf2 and heme oxygenase 1 in livers of DDC-treated mice.A: Nrf2 protein expression and (B) densitometry in hepatic nuclear fractions. The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (Lamin A/C) C: Heme oxygenase-1 (HO-1) protein expression and (D) densitometry in total liver homogenate (HO-1) and mitochondrial fractions (mtHO-1). The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (calnexin for total homogenate, Ponceau S for the mitochondrial fraction). (E) Activities of HO-1 in microsomes and mtHO-1 in mitochondria as pmol bilirubin/mg protein/h.

Mentions: Nrf2 protein levels in nuclear fractions, indicating antioxidant response [18], [19], revealed two peaks, at week 2 and week 8 of DDC intoxication (Fig. 5A, 5B). A similar biphasic pattern was observed with the downstream Nrf2-targets Nqo1 (not shown) and HO-1 (Fig. 5C, 5D).


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)

Expression of Nrf2 and heme oxygenase 1 in livers of DDC-treated mice.A: Nrf2 protein expression and (B) densitometry in hepatic nuclear fractions. The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (Lamin A/C) C: Heme oxygenase-1 (HO-1) protein expression and (D) densitometry in total liver homogenate (HO-1) and mitochondrial fractions (mtHO-1). The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (calnexin for total homogenate, Ponceau S for the mitochondrial fraction). (E) Activities of HO-1 in microsomes and mtHO-1 in mitochondria as pmol bilirubin/mg protein/h.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675145&req=5

pone-0066094-g005: Expression of Nrf2 and heme oxygenase 1 in livers of DDC-treated mice.A: Nrf2 protein expression and (B) densitometry in hepatic nuclear fractions. The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (Lamin A/C) C: Heme oxygenase-1 (HO-1) protein expression and (D) densitometry in total liver homogenate (HO-1) and mitochondrial fractions (mtHO-1). The intensity of protein bands was quantified, and individual blot densities were normalized to loading control (calnexin for total homogenate, Ponceau S for the mitochondrial fraction). (E) Activities of HO-1 in microsomes and mtHO-1 in mitochondria as pmol bilirubin/mg protein/h.
Mentions: Nrf2 protein levels in nuclear fractions, indicating antioxidant response [18], [19], revealed two peaks, at week 2 and week 8 of DDC intoxication (Fig. 5A, 5B). A similar biphasic pattern was observed with the downstream Nrf2-targets Nqo1 (not shown) and HO-1 (Fig. 5C, 5D).

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