Glial cell line-derived neurotrophic factor-induced mice liver defatting: A novel strategy to enable transplantation of steatotic livers

• Type of Material: Article
• Authors: Sahar Taba Taba Vakili, Emory University; Roshni Kailar, Emory University; Khalidur Rahman, Emory University; Behtash Ghazi Nezami, Emory University; Simon Mwangi, Emory University; Frank Anania, Emory University; Shanthi Srinivasan, Emory University
• Language: English
• Date: 2016-04-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2015 by the American Association for the Study of Liver Diseases; This is the peer reviewed version of the following article: [Vakili, Sahar Taba Taba et al. “Glial Cell Line-Derived Neurotrophic Factor Induced Mice Liver Defatting: A Novel Strategy to Enable Transplantation of Steatotic Livers.” Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 22.4 (2016): 459–467. PMC. Web. 20 Apr. 2017.], which has been published in final form at [http://onlinelibrary.wiley.com/doi/10.1002/lt.24385/epdf]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
• Final Published Version (URL): http://dx.doi.org/10.1002/lt.24385
• Title of Journal or Parent Work: Liver Transplantation
• ISSN: 1527-6465
• Volume: 22
• Issue: 4
• Start Page: 459
• End Page: 467
• Grant/Funding Information: U.S. National Institutes of Health (NIH) grant NIH-RO1 DK080684 to SS, DK062092 to FAA, and VA-MERIT award to SS and FAA.
• Keywords: INCREASES; PERFUSION; EXPRESSION; FATTY LIVER; SENSITIVITY; Gastroenterology & Hepatology; Surgery; HEPATOCYTES; Science & Technology; Life Sciences & Biomedicine; RAT; DONOR ORGANS; HEPATIC STEATOSIS; Transplantation; INJURY
• Research Categories: Health Sciences, Medicine and Surgery; Engineering, Biomedical

Abstract

Moderate macrovesicular steatosis (>30%), which is present in almost 50% of livers considered for transplantation increases the risk of primary graft dysfunction. Our previously published data showed that glial cell line-derived neurotrophic factor (GDNF) is protective against high-fat diet (HFD)-induced hepatic steatosis in mice. Hence, we hypothesized that perfusion of steatotic livers with GDNF may reduce liver fat content prior to transplantation. Livers from 8 weeks regular diet (RD) and HFD-fed mice were perfused ex-vivo for 4 hours with either vehicle, GDNF, or a previously described defatting cocktail. Liver’s residual fat was quantified colorimetrically using a triglyceride assay kit, and by Oil Red-O and Nile Red/Hoechst staining. Liver tissue injury was assessed using an LDH activity assay. In vitro induction of lipolysis in HepG2 cells was assessed by measuring glycerol and free fatty acid release. Oil Red-O staining showed significantly more steatosis in liver from HFD-fed mice compared with RD-fed mice (P<0.001). HFD Livers perfused with GDNF had significantly less steatosis than those not perfused (P=0.001) or perfused with vehicle (P<0.05). GDNF is equally effective in steatotic liver defatting compared to the defatting cocktail; however, GDNF induces less liver damage than the defatting cocktail. These observations were consistent with data obtained from assessment of liver triglyceride content. Assessment of liver injury revealed significant hepatocyte injury in livers perfused with the control defatting cocktail but no evidence of injury in livers perfused with either GDNF or vehicle. In vitro, GDNF reduced triglyceride accumulation in HepG2 cells and stimulated increased triglyceride lipolysis.