Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo.
OBJECTIVE
During hepatic fibrosis, hepatic stellate cells (HSCs) transform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. Recently, we have demonstrated that 9,13-di-cis-retinoic acid (RA), a geometric isomer identified as a stable and major metabolite of vitamin A in circulation, stimulates the synthesis of plasminogen activator (PA) and induces PA/plasmin-dependent latent transforming growth factor (TGF)-beta activation in HSC cultures, probably via induction and activation of RA receptor (RAR) alpha. The aim of the present study was to address a potential link between the loss of retinyl esters to increased formation of RA(s), which might play a role in facilitating TGF-beta-mediated liver fibrogenesis in vivo.


METHODS
We examined the effect of 9,13-di-cis-RA on transactivating activity of RARalpha in HeLa cells as well as its effect on PA- and TGF-beta-dependent collagen synthesis in rat and human HSC cultures. We measured the changes in 9,13-di-cis-RA levels both during activation of rat HSCs in vitro and during porcine serum-induced rat hepatic fibrosis in vivo and correlated this with RAR alpha/beta, PA, TGF-beta and type I procollagen mRNA expression in the fibrotic liver.


RESULTS
9,13-di-cis-RA transactivated RARalpha, and provoked PA/plasmin and TGF-beta-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were increased both in activated HSCs in vitro and in fibrotic liver accompanying the enhanced expression of RAR alpha/beta, PA, TGF-beta and procollagen in vivo.


CONCLUSIONS
These findings suggest a potential link between 9,13-di-cis RA formation and hepatic fibrosis via formation of TGF-beta in vivo, and thus provide further insight into the biologic role of retinoids during hepatic fibrogenesis.
Okuno
M
M
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Sato
T
T
Kitamoto
T
T
Imai
S
S
Kawada
N
N
Suzuki
Y
Y
Yoshimura
H
H
Moriwaki
H
H
Onuki
K
K
Masushige
S
S
Muto
Y
Y
Friedman
S L
SL
Kato
S
S
Kojima
S
S
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000166:cytology*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D010960:Plasminogen Activators / Q000502:physiology; D011347:Procollagen / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000502:physiology; D012176:Retinoids / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism
D011347:Procollagen; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D016212:Transforming Growth Factor beta; C105492:9,13-retinoic acid; D014212:Tretinoin; D012313:RNA; D003094:Collagen; D010960:Plasminogen Activators