Fat-derived hormone adiponectin combined with FTY720 significantly improves small-for-size fatty liver graft survival.
Owing to the discrepancy between organ donation and the demand for liver transplantation, expanding the liver donor pool is of vital importance. However, marginal liver grafts, such as small-for-size and/or fatty grafts, were associated with primary graft nonfunction or poor function. Therefore, novel combination therapies to rescue small-for-size fatty liver grafts should be investigated. In this study, we applied a combination therapy using a fat-derived hormone adiponectin (anti-steatosis) plus immunomodulator FTY720 (anti-inflammatory) in a rat liver transplantation model using small-for-size fatty liver grafts, and investigated the underlying protective mechanism such as anti-steatosis, intra-graft energy metabolism, hepatic microcirculatory changes, cell signaling cascades for survival, apoptosis and inflammation. The current study demonstrated that even a single treatment of adiponectin or FTY720 improved the 7-day graft survival from 0% to 62.5% (p = 0.001). The combination therapy significantly increased the 7-day graft survival rate to 100% by remarkable attenuation of graft steatosis and acute phase inflammatory response, significant activation of cell survival Akt pathway and maintenance of intra-graft adenosine triphosphate metabolism and improvement of hepatic microcirculation. In conclusion, the fat-derived hormone adiponectin combined with FTY720 might be a novel combination drug therapy for prevention of small-for-size fatty liver graft injury.
Man
K
K
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China. kwanman@hkucc.hku.hk
Zhao
Y
Y
Xu
A
A
Lo
C M
CM
Lam
K S L
KS
Ng
K T
KT
Ho
J W Y
JW
Sun
C K
CK
Lee
T K
TK
Li
X L
XL
Fan
S T
ST
D052242:Adiponectin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000473:pathology / Q000601:surgery*; D000068876:Fingolimod Hydrochloride; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016031:Liver Transplantation; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
D052242:Adiponectin; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine