Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats

Uchino, Shigehiko; Yamaguchi, Yasuo; Furuhashi, Takashi; Wang, Fengshan; Zhang, Jialin; Okabe, Kazutoshi; Kihara, Shinichi; Yamada, Shinwa; Mori, Katsutaka; Ogawa, Michio

doi:10.1016/j.jss.2003.10.010

Cited by 26 publications

(18 citation statements)

References 85 publications

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“…Excess storage of intracellular lipids in hepatocytes has been reported to increase sensitivity to select apoptosis-causing signals (31). The mechanism whereby steatosis reduced the mitochondrial membrane potential was not investigated in this study; however, in vivo studies of steatotic livers have reported increased expression of mitochondrial uncoupling protein-2 (UCP-2), which decouples the respiratory chain from the ATP synthase (32). Furthermore, treatments that decrease lipid content, such as epigallocatechin gallate administration, also decrease UCP-2 levels and ischemia-reperfusion-induced hepatic damage (33).…”

Section: Discussionmentioning

confidence: 91%

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Berthiaume

Barbe

Mokuno

et al. 2009

Journal of Surgical Research

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Section: Discussionmentioning

confidence: 91%

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Berthiaume

Barbe

Mokuno

et al. 2009

Journal of Surgical Research

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“…It has been shown that hepatocyte steatosis predisposes livers to the development of necrosis and inflammatory changes after transplantation. 30 Liver injury under these circumstances is likely induced by LPS released from the gut. 29,[31][32][33] PHx, used here as an experimental model, is also associated with an increased concentration of gutderived LPS in the portal blood.…”

Section: Discussionmentioning

confidence: 99%

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

et al. 2005

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Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in welldeveloped Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (I B␣) expression, which inhibited nuclear factor-kappa B (NF-B) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through I B␣ overexpression and subsequent NF-B inhibition.

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“…Because some of the effects of UCP2 in these models were attributed to the reduction of oxidative injury, a deficiency in the expression of UCP2 could exacerbate the inevitable oxidative stress associated with liver I/R. However, in steatotic livers subjected to ischemia, UCP2 expression was shown to be directly proportional to injury, including necrosis (7,25). Because UCP2 is highly expressed in steatotic livers and is capable of causing partial mitochondrial depolarization, we considered that UCP2 promotes hepatocellular death during periods of limited ATP availability as seen in liver I/R, rather than protecting from oxi-* This work was supported by National Institutes of Health Grants 1R01DK069369 and 5P20RR017677-05.…”

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confidence: 99%

Mitochondrial Uncoupling Protein-2 Mediates Steatotic Liver Injury following Ischemia/Reperfusion

Evans¹,

Ellett²,

Schmidt³

et al. 2008

Journal of Biological Chemistry

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Steatotic livers are not used for transplantation because they have a reduced tolerance for ischemic events with reduced ATP levels and greater levels of cellular necrosis, which ultimately result in total organ failure. Mitochondrial uncoupling protein-2 (UCP2) is highly expressed in steatotic livers and may be responsible for liver sensitivity to ischemia through mitochondrial and ATP regulation. To test this hypothesis, experiments were conducted in lean and steatotic (ob/ob), wild-type, and UCP2 knock-out mice subjected to total warm hepatic ischemia/reperfusion. Although ob/ob UCP2 knock-out mice and ob/ob mice have a similar initial phenotype, ob/ob UCP2 knock-out animal survival was 83% when compared with 30% in ob/ob mice 24 h after reperfusion. Serum alanine aminotransferase concentrations and hepatocellular necrosis were decreased in the ob/ob UCP2 knock-out mice when compared with ob/ob mice subjected to ischemia. Liver ATP levels were increased in the ob/ob UCP2 knock-out animals after reperfusion when compared with the ob/ob mice but remained below the concentrations from lean livers. Lipid peroxidation (thiobarbituric acid-reactive substances) increased after reperfusion most significantly in the steatotic groups, but the increase was not affected by UCP2 deficiency. These results reveal that UCP2 expression is a critical factor, which sensitizes steatotic livers to ischemic injury, regulating liver ATP levels after ischemia and reperfusion.Complications from liver steatosis represent a significant clinical concern, especially for liver surgeries including resection and transplantation. This is of escalating importance as nonalcoholic fatty liver disease is independently correlated to obesity and insulin resistance, which are both epidemic in the Unites States (1, 2). Steatotic livers are considerably more sensitive to acute stressors including ischemia/reperfusion (I/R) 2 as experienced in transplantation, and organs meeting this criterion are routinely turned down for donation (3-6). Under I/R conditions, steatotic livers are ATP-depleted, and the predominant hepatocellular fate is shifted from apoptosis to oncotic necrosis, strongly implicating inappropriate energy homeostasis as the primary cause of liver sensitivity (7-10).In a state of energy substrate abundance and forward shift in cellular redox potential, hepatocytes are thought to combat mitochondrial electron transport chain-derived reactive oxygen species (ROS) production through mitochondrial uncoupling. In normal lean livers, mitochondrial uncoupling protein-2 (UCP2) is confined to Kupffer cells; however, hepatocellular concentrations of UCP2 greatly increase with steatosis (7,11,12). Although the mechanism is not known, UCP2 facilitates passive proton conductance across the mitochondrial inner membrane into the matrix during respiration (13,14). Maximum employment of electrochemical potential at ATP synthase is sacrificed by UCP2, and heat, rather than ATP, is produced. Proton conductance is thought to require posttranslational activ...

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Steatotic liver allografts up-regulate UCP-2 expression and suffer necrosis in rats

Cited by 26 publications

References 85 publications

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

Mitochondrial Uncoupling Protein-2 Mediates Steatotic Liver Injury following Ischemia/Reperfusion

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