Fatty acid synthase blockade protects steatotic livers from warm ischemia reperfusion injury and transplantation.
Cerulenin has been shown to reduce body weight and hepatic steatosis in murine models of obesity by inhibiting fatty acid synthase (FAS). We have shown that attenuating intrahepatocyte lipid content diminished the sensitivity of ob/ob mice to ischemia/reperfusion injury and improved survival after liver transplantation. The mechanism of action is by inhibition of fatty acid metabolism by downregulating PPARalpha, as well as mitochondrial uncoupling protein 2 (UCP2), with a concomitant increase in ATP. A short treatment course of cerulenin prior to I/R injury is ideal for protection of steatotic livers. Cerulenin opens the potential for expanding the use of steatotic livers in transplantation.
Department of Surgery, Division of Transplant, Medical University of South Carolina (MUSC), Charleston, SC, USA. chavinkd@musc.edu
Kenneth D
KD
Chavin
Ryan N
RN
Fiorini
Stephen
S
Shafizadeh
Gang
G
Cheng
Chidan
C
Wan
Zachary
Z
Evans
David
D
Rodwell
Carmen
C
Polito
Julia K
JK
Haines
G Mark
GM
Baillie
Michael G
MG
Schmidt
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D002108:Ceruletide / Q000627:therapeutic use*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000503:physiopathology*; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015427:Reperfusion Injury / Q000517:prevention & control*
D005227:Fatty Acids; D002108:Ceruletide; D000255:Adenosine Triphosphate; D064429:Fatty Acid Synthases; D000410:Alanine Transaminase