PPARα is down-regulated following liver transplantation in mice.
OBJECTIVE
Graft dysfunction is one of the major complications after liver transplantation, but its precise mechanism remains unclear. Since steatotic liver grafts are susceptible to post-transplant dysfunction, and peroxisome proliferator-activated receptor (PPAR) α plays an important role in the maintenance of hepatic lipid homeostasis, we examined the role of PPARα in liver transplantation.


METHODS
Livers were harvested from Sv/129 wild-type (Ppara(+/+)) mice and PPARα-null (Ppara(-/-)) mice and transplanted orthotopically into syngeneic Ppara(+/+) mice.


RESULTS
Hepatocellular damage was unexpectedly milder in transplanted Ppara(-/-) livers compared with Ppara(+/+) ones. This was likely due to decreased lipid peroxides in the Ppara(-/-) livers, as revealed by the lower levels of fatty acid oxidation (FAO) enzymes, which are major sources of reactive oxygen species. Hepatic PPARα and its target genes, such as FAO enzymes and pyruvate dehydrogenase kinase 4, were strongly down-regulated after transplantation, which was associated with increases in hepatic tumor necrosis factor-α expression and nuclear factor-κB activity. Inhibiting post-transplant PPARα down-regulation by clofibrate treatment markedly augmented oxidative stress and hepatocellular injury.


CONCLUSIONS
Down-regulation of PPARα seemed to be an adaptive response to metabolic alterations following liver transplantation. These results provide novel information to the understanding of the pathogenesis of early post-transplant events.
Department of Metabolic Regulation, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
Kan
K
Nakagawa
Naoki
N
Tanaka
Miwa
M
Morita
Atsushi
A
Sugioka
Shin-ichi
S
Miyagawa
Frank J
FJ
Gonzalez
Toshifumi
T
Aoyama
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002952:Citric Acid Cycle / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D055031:Primary Graft Dysfunction / Q000378:metabolism* / Q000503:physiopathology*
D047493:PPAR alpha; D000105:Acetyl Coenzyme A