TY - JOUR
T1 - Metabolic preconditioning of donor organs
T2 - Defatting fatty livers by normothermic perfusion ex vivo
AU - Nagrath, Deepak
AU - Xu, Hongzhi
AU - Tanimura, Yoko
AU - Zuo, Rongjun
AU - Berthiaume, François
AU - Avila, Marco
AU - Yarmush, Rubin
AU - Yarmush, Martin L.
N1 - Funding Information:
Financial support: This work was partially supported by the National Institutes of Health Grant nos. R01DK059766, R01DK43371, P41EB002503, and the Shriners Hospitals for Children.
PY - 2009/7
Y1 - 2009/7
N2 - Fatty liver is a significant risk factor for liver transplantation, and accounts for nearly half of the livers rejected from the donor pool. We hypothesized that metabolic preconditioning via ex vivo perfusion of the liver graft can reduce fat content and increase post-transplant survival to an acceptable range. We describe a perfusate medium containing agents that promote the defatting of hepatocytes and explanted livers. Defatting agents were screened on cultured hepatocytes made fatty by pre-incubation with fatty acids. The most effective agents were then used on fatty livers. Fatty livers were isolated from obese Zucker rats and normothermically perfused with medium containing a combination of defatting agents. This combination decreased the intracellular lipid content of cultured hepatocytes by 35% over 24 h, and of perfused livers by 50% over 3 h. Metabolite analysis suggests that the defatting cocktail upregulated both lipid oxidation and export. Furthermore, gene expression analysis for several enzymes and transcription factors involved in fatty acid oxidation and triglyceride clearance were elevated. We conclude that a cocktail of defatting agents can be used to rapidly clear excess lipid storage in fatty livers, thus providing a new means to recondition donor livers deemed unacceptable or marginally acceptable for transplantation.
AB - Fatty liver is a significant risk factor for liver transplantation, and accounts for nearly half of the livers rejected from the donor pool. We hypothesized that metabolic preconditioning via ex vivo perfusion of the liver graft can reduce fat content and increase post-transplant survival to an acceptable range. We describe a perfusate medium containing agents that promote the defatting of hepatocytes and explanted livers. Defatting agents were screened on cultured hepatocytes made fatty by pre-incubation with fatty acids. The most effective agents were then used on fatty livers. Fatty livers were isolated from obese Zucker rats and normothermically perfused with medium containing a combination of defatting agents. This combination decreased the intracellular lipid content of cultured hepatocytes by 35% over 24 h, and of perfused livers by 50% over 3 h. Metabolite analysis suggests that the defatting cocktail upregulated both lipid oxidation and export. Furthermore, gene expression analysis for several enzymes and transcription factors involved in fatty acid oxidation and triglyceride clearance were elevated. We conclude that a cocktail of defatting agents can be used to rapidly clear excess lipid storage in fatty livers, thus providing a new means to recondition donor livers deemed unacceptable or marginally acceptable for transplantation.
KW - Hepatocytes
KW - Liver transplantation
KW - Normothermic perfusion
KW - Nuclear receptors
KW - Steatosis
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U2 - 10.1016/j.ymben.2009.05.005
DO - 10.1016/j.ymben.2009.05.005
M3 - Article
C2 - 19508897
AN - SCOPUS:68249104194
VL - 11
SP - 274
EP - 283
JO - Metabolic Engineering
JF - Metabolic Engineering
SN - 1096-7176
IS - 4-5
ER -