Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

Shankar, Kartik; Vaidya, Vishal S.; Corton, J. Christopher; Bucci, Thomas J.; Liu, Jie; Waalkes, Michael P.; Mehendale, Harihara M.

doi:10.1096/fj.02-1186fje

Cited by 60 publications

(46 citation statements)

References 57 publications

(91 reference statements)

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“…Studies in diabetic mice have demonstrated that increased PPAR-␣ activation provide protection against acute hepatotoxicity from acetaminophen as the result of increased hepatocyte proliferation in response to toxic challenge associated with upregulation of cyclin D 1 (43). This protection was abolished in diabetic PPAR-␣ knockout mice (43). A similar mechanism may underlie the increased hepatocyte proliferation observed with EtOH treatment in underfed rats in the present study.…”

Section: Discussionsupporting

confidence: 65%

“…This suggests a positive role for PPAR-␣ in the regulation of hepatocyte proliferation. Studies in diabetic mice have demonstrated that increased PPAR-␣ activation provide protection against acute hepatotoxicity from acetaminophen as the result of increased hepatocyte proliferation in response to toxic challenge associated with upregulation of cyclin D 1 (43). This protection was abolished in diabetic PPAR-␣ knockout mice (43).…”

Section: Discussionmentioning

confidence: 99%

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Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

Baumgardner¹,

Shankar²,

Korourian³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 or 154 kcal·kg−3/4·day−1 with or without 11 g·kg−1·day−1 EtOH. EtOH clearance was impaired in the 154 kcal·kg−3/4·day−1 EtOH group ( P ≤ 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (CYP)2E1 and CYP4A1 mRNA, apoprotein, and activities ( P ≤ 0.05). This was accompanied by increased oxidative stress ( P ≤ 0.05). The severity of liver steatosis, macrophage infiltration, and focal necrosis was comparable in both EtOH groups. Alanine aminotransferase levels were elevated ( P ≤ 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups ( P ≤ 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal·kg−3/4·day−1 but at 154 kcal·kg−3/4·day−1 was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-α (PPAR-α)-regulated FA degradation pathways ( P ≤ 0.05). In addition, 154 kcal·kg−3/4·day−1 EtOH group livers exhibited greater hepatocyte proliferation ( P ≤ 0.05). We conclude that undernutrition does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR-α signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

Baumgardner¹,

Shankar²,

Korourian³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The effect of CR diets on Hsps, inflammatory cascades and PPAR activity have been well documented (Nguyen et al, 1999;Yu and Chung, 2001;Shankar et al, 2003;Tsuchiya et al, 2005), and are consistent with the increased ability of these mice to resist xenobiotic insults. In dwarf mouse models, it has been shown that constitutive PPAR-α activity and its related gene products is increased (Stauber et al, 2005;Masternak et al, 2005), and that Ames dwarf mice exhibit an enhanced resistance to paraquat-induced lethality (Bartke et al, 2001a) while GHR-KO mice are relatively sensitive to paraquat-induced death (Hauck et al, 2002); however little else is known about xenobiotic metabolism in these mouse models.…”

Section: Discussionsupporting

confidence: 53%

“…The pathogenesis of liver cell death in response to acetaminophen (APAP) is multifaceted, and in addition to intrinsic hepatocyte responses to APAP metabolites, is influenced by proinflammatory cytokine cascades (Laskin and Laskin, 2001), heat shock proteins (Hsp) (Tolson et al, 2006), and peroxisome proliferator activated receptor (PPAR)-α activity (Nguyen et al, 1999;Shankar et al, 2003). The hepatic level of reduced glutathione is also an important factor in APAP-induced damage (Oz et al, 2005) and may contribute to some of the animal-to-animal variation in the response to APAP.…”

Section: Discussionmentioning

confidence: 99%

Stress resistance and aging: Influence of genes and nutrition

Harper

Salmon

Chang

et al. 2006

Mechanisms of Ageing and Development

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Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf (dw/dw), Ames dwarf (df/df) and growth hormone receptor knockout (GHR-KO) mouse stocks are resistant, in vitro, to the cytotoxic effects of hydrogen peroxide, cadmium, ultraviolet light, paraquat, and heat. Here we show that, in contrast, fibroblasts from mice on low-calorie (CR) or low methionine (Meth-R) diets are not stress resistant in culture, despite the longevity induced by both dietary regimes. A second approach, involving induction of liver cell death in live animals using acetaminophen (APAP), documented hepatotoxin resistance in the CR and Meth-R mice, but dw/dw and GHR-KO mutant mice were not resistant to this agent, and were in fact more susceptible than littermate controls to the toxic effects of APAP. These data thus suggest that while resistance to stress is a common characteristic of experimental life span extension in mice, the cell types showing resistance may differ among the various models of delayed or decelerated aging.

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“…In stark contrast, type 1 DB mice challenged with TA and acetaminophen (APAP) exhibit higher hepatic tissue repair (Shankar et al, 2003a) and higher renal tissue repair after challenge with 1,2-dichlorovinyl-L-cysteine . It is known that hepatoprotection in type 1 DB mice is dependent on PPAR-␣ activation (Shankar et al, 2003b).…”

mentioning

confidence: 99%

Protective Effect of Type 2 Diabetes on Acetaminophen-Induced Hepatotoxicity in Male Swiss-Webster Mice

Sawant

Dnyanmote²,

Mitra³

et al. 2005

J Pharmacol Exp Ther

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Type 2 diabetic (DB) mice exposed to CCl 4 (LD 50 ϭ 1.25 ml/kg), acetaminophen (LD 80 ϭ 600 mg/kg; APAP), and bromobenzene (LD 80 ϭ 0.5 ml/kg) i.p. yielded 30, 20, and 20% mortality, respectively, indicating hepatotoxic resistance. Male SwissWebster mice were made diabetic by feeding high fat and administrating streptozotocin (120 mg/kg i.p.) on day 60. On day 71, time-course studies after APAP (600 mg/kg) treatment revealed identical initial liver injury in non-DB and DB mice, which progressed only in non-DB mice, resulting in 80% mortality. The hypothesis that decreased APAP bioactivation, altered toxicokinetics, and/or increased tissue repair are the underlying mechanisms was investigated. High-performance liquid chromatography analysis revealed no difference in plasma and urinary APAP or detoxification of APAP via glucuronidation between DB and non-DB mice. Hepatic CYP2E1 protein and activity, glutathione, and [14 C]APAP covalent binding did not differ between DB and non-DB mice, suggesting that lower bioactivation-based injury is not the mechanism of decreased hepatotoxicity in DB mice. Diabetes increased cells in S phase by 8-fold in normally quiescent liver of these mice. Immunohistochemistry revealed overexpression of calpastatin in the newly dividing/divided cells, explaining inhibition of hydrolytic enzyme calpain in perinecrotic areas and lower progression of APAP-initiated injury in the DB mice. Antimitotic intervention of diabetes-associated cell division with colchicine before APAP administration resulted in 70% mortality in APAPtreated colchicine-intervened DB mice. These studies suggest that advancement of cells in the cell division cycle and higher tissue repair protect DB mice by preventing progression of APAP-initiated liver injury that normally leads to mortality.

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Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

Cited by 60 publications

References 57 publications

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

Stress resistance and aging: Influence of genes and nutrition

Protective Effect of Type 2 Diabetes on Acetaminophen-Induced Hepatotoxicity in Male Swiss-Webster Mice

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