title: Metabolic preconditioning of donor organs: defatting fatty livers by normothermic perfusion ex vivo.
abstract: 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 24h, and of perfused livers by 50% over 3h. 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.
authors.affiliation: Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and the Shriners Hospitals for Children, Boston, MA 02114, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Xu
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanimura
authors.forename: Rongjun
authors.initials: R
authors.lastname: Zuo
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Marco
authors.initials: M
authors.lastname: Avila
authors.forename: Rubin
authors.initials: R
authors.lastname: Yarmush
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival; D002478:Cells, Cultured; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000166:cytology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016031:Liver Transplantation; D010477:Perfusion / Q000379:methods*; D051381:Rats; D011917:Rats, Inbred Lew; D011924:Rats, Zucker; D016019:Survival Analysis; D013997:Time Factors; D014019:Tissue Donors