Geranylgeranylacetone prevents acute liver damage after massive hepatectomy in rats through suppression of a CXC chemokine GRO1 and induction of heat shock proteins.
METHODS
Acute liver failure after massive hepatectomy remains a challenging problem. In this study, using a microarray designed to monitor the side effects of drugs, we examined changes in gene expression in the remnant liver during the 24 h after hepatectomy and the effects of a nontoxic heat shock protein (HSP) 70 inducer, geranylgeranylacetone (GGA), after 90% hepatectomy in rats.


RESULTS
A single oral administration of 100 mg/kg GGA significantly suppressed the release of aminotransferases and improved survival compared with vehicle administration. The hepatectomy upregulated 74 genes and downregulated 95. Interestingly, ten cytokine genes were upregulated, while no cytokine-related gene was downregulated. Among the ten cytokine genes, a potent chemoattractant for neutrophils, GRO1, was most rapidly and markedly upregulated after 90% hepatectomy. GGA effectively suppressed the up-regulation of GRO1 messenger ribonucleic acid, and this was validated by Northern hybridization. Microarray and immunoblot analyses showed that, in addition to HSP70 and HSP27, GGA preferentially induced an endoplasmic reticulum chaperone, BIP.


CONCLUSIONS
Considering hemodynamic and metabolic overloading as a primary cause of acute lever failure, the ER stress response enhanced by GGA may also play an important role in the prevention of overload-induced liver damage.
Kanemura
Hirofumi
H
Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Kusumoto
Kenji
K
Miyake
Hidenori
H
Tashiro
Seiki
S
Rokutan
Kazuhito
K
Shimada
Mitsuo
M
D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001345:Autoradiography; D015153:Blotting, Western; D054360:Chemokine CXCL1 / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D006498:Hepatectomy / Q000009:adverse effects*; D017114:Liver Failure, Acute / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D046228:Microarray Analysis; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000897:Anti-Ulcer Agents; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D012313:RNA; C031049:geranylgeranylacetone