Fatty Acid Synthase Blockade Protects Steatotic Livers from Warm Ischemia Reperfusion Injury and Transplantation

Chavin, Kenneth D.; Fiorini, Ryan N.; Shafizadeh, Stephen; Cheng, Gang; Wan, Cheng; Evans, Zachary; Rodwell, David W.; Polito, Carmen; Haines, Julia K.; Baillie, G. Mark; Schmidt, Michael G.

doi:10.1111/j.1600-6143.2004.00546.x

Cited by 53 publications

(55 citation statements)

References 19 publications

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“…Since the extent of steatosis is positively associated with the extent of IRI (7,8,39,40), and the C3 activation product C3adesArg (also known as acylation-stimulating protein) is involved in the regulation of lipid metabolism (41,42), a possible explanation for the reduced level of hepatic IRI seen in C3 Ϫ/Ϫ mice is that C3 Ϫ/Ϫ mice develop less liver steatosis. However, following a 4-wk high fat diet (60% calories from fat), we detected no significant quantitative or qualitative differences in steatosis between wt and C3 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

Atkinson²,

Evans

et al. 2009

The Journal of Immunology

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Hepatic steatosis typically renders the donor organ unusable, as donor organs with >30% steatosis are more likely to develop graft failure. The mechanisms leading to failure are not well defined, but steatosis enhances hepatic susceptibility to ischemia reperfusion injury (IRI). We investigated the role of complement in hepatic IRI in lean and steatotic (diet-induced) mice. Steatotic mice were significantly more susceptible to total warm hepatic IRI than lean mice as determined by serum alanine aminotransferase, histopathologically assessed damage, and 24-h survival. C3 deficiency protected both lean and steatotic mice from IRI, as determined by all measured outcomes. Furthermore, treatment of wild-type mice with the complement inhibitor CR2-Crry provided protection equivalent to that seen in C3-deficient mice. Importantly, although steatotic livers were much more susceptible to IRI than lean livers, by most measures there was no statistical difference between the level of IRI to steatotic or lean livers when complement was inhibited. To investigate the clinical relevance of these findings in the context of transplantation, we treated recipients of lean or steatotic liver grafts with saline or CR2-Crry. There was a marked reduction in graft inflammation and injury and significantly improved 7-day survival in CR2-Crry-treated recipients of either lean or steatotic grafts. These data indicate that complement plays a key role in the enhanced susceptibility of steatotic livers to IRI and suggest that complement inhibition represents a potential strategy to reduce the donor shortage by allowing the more routine use of marginal steatotic donor livers.

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Section: Discussionmentioning

confidence: 99%

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

Atkinson²,

Evans

et al. 2009

The Journal of Immunology

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“…Consequently, interventions that reduce intracellular lipid content in hepatocytes may be a potential avenue to precondition steatotic livers before surgical interventions that involve stopping blood flow for significant periods of time, such as in transplantation procedures. Such interventions could be implemented in the donor prior to liver explantation (34), or in a normothermic perfusion system (35). The cell culture system described herein may be useful to screen various metabolic treatments or preconditioning strategies to increase the resistance of steatotic hepatocytes to hypoxia-reoxygenation injury prior to testing in more complex animal models.…”

Section: Discussionmentioning

confidence: 99%

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Berthiaume

Barbe

Mokuno

et al. 2009

Journal of Surgical Research

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“…2,3 Fatty liver is also more susceptible to acute injury such as ischemia-reperfusion and endotoxinemia. 4,5 In a pilot study on patients with biopsy-proven nonalcoholic steatohepatitis, recovery from hepatic adenosine triphosphate (ATP) depletion induced by intravenously given fructose was less efficient than in healthy controls, suggesting impaired hepatic energy homeostasis in fatty liver disease. 6 Although a follow-up study on healthy volunteers could not confirm a similar connection, baseline hepatic ATP stores in these individuals inversely correlated with higher body mass index.…”

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Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

et al. 2006

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Fatty liver is vulnerable to conditions that challenge hepatocellular energy homeostasis. Lipidladen hepatocytes highly express uncoupling protein-2 (UCP2), a mitochondrial carrier that competes with adenosine triphosphate (ATP) synthesis by mediating proton leak. However, evidence for a link between UCP2 expression and susceptibility of liver to acute injury is lacking. We asked whether absence of UCP2 protects ob/ob mice from Fas-mediated acute liver damage. UCP2-deficient ob/ob mice (ob/ob:ucp2 ؊/؊ ) and UCP2-competent littermates (ob/ob:ucp2 ؉/؉ ) received a single dose of agonistic anti-Fas antibody (Jo2). Low-dose Jo2 (0.15 mg/kg intraperitoneally) caused less serum alanine aminotransferase (ALT) elevation and lower apoptosis rates in ob/ob:ucp2 ؊/؊ mice. High-dose Jo2 (0.40 mg/kg intraperitoneally) proved uniformly fatal; however, ob/ob:ucp2 ؊/؊ mice survived longer with less depletion of liver ATP stores, indicating that fatty hepatocytes may benefit from lack of UCP2 during Jo2 challenge. Although UCP2 reportedly controls mitochondrial oxidant production, its absence had no apparent effect on fatty liver tissue malondialdehyde levels augmented by Jo2. This finding prompted us to determine UCP2 expression in Kupffer cells, a major source of intrahepatic oxidative stress. UCP2 expression was found diminished in Kupffer cells of untreated ob/ob:ucp2 ؉/؉ mice, conceivably contributing to increased oxidative stress in fatty liver and limiting the impact of UCP2 ablation. In conclusion, whereas UCP2 abundance in fatty hepatocytes exacerbates Fas-mediated injury by compromising ATP stores, downregulation of UCP2 in Kupffer cells may account for persistent oxidative stress in fatty liver. Our data support a cell-specific approach when considering the therapeutic effects of mitochondrial uncoupling in fatty liver disease. (HEPATOLOGY 2006;44:592-601.)

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Fatty Acid Synthase Blockade Protects Steatotic Livers from Warm Ischemia Reperfusion Injury and Transplantation

Cited by 53 publications

References 19 publications

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

A Role for Complement in the Enhanced Susceptibility of Steatotic Livers to Ischemia and Reperfusion Injury

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Lack of UCP2 reduces fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression

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