Elevated concentrations of 15-deoxy-Delta12,14-prostaglandin J2 in chronic liver disease propose therapeutic trials with peroxisome proliferator activated receptor gamma-inducing drugs.
OBJECTIVE
Current knowledge confers a crucial role to connective tissue growth factor (CTGF/CCN2) in hepatic fibrogenesis. Hepatocytes are likely to be the major cellular source of CTGF in the liver in which CTGF is sensitively upregulated by TGF-beta. Recently, we demonstrated that the methylxanthine derivate caffeine leads to an upregulation of peroxisome proliferator activated receptor gamma (PPARgamma) expression in hepatocytes, thus sensitizing these cells to the well-known inhibitory effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)) on CTGF expression. However, upregulation of the receptor alone is not sufficient per se; its physiological ligand 15-d-PGJ(2) is required to exert an inhibitory effect on transforming growth factor-beta (TGF-beta) target genes such as CTGF.


METHODS
This study compared serum concentrations of 15-d-PGJ(2) in Caucasian patients with fibrotic liver diseases (n=289), Caucasian controls (n=136) and Caucasian non-liver disease (NLD) sick (n=307), as well as of Chinese patients with hepatocellular carcinoma (HCC) (n=43) and Chinese healthy controls (n=63) in order to characterize their suitability for therapeutic approaches with PPARgamma-inducing (i.e. CTGF inhibitory) drugs such as caffeine.


RESULTS
The presented data showed that Caucasian patients with ongoing hepatic fibrogenesis (mean 6.2+/-5.9 microg/L) displayed strikingly higher serum concentrations of 15-d-PGJ(2) than healthy probands (mean 2.3+/-1.0) and Caucasian patients with NLD (mean 2.7+/-1.4 microg/L). Similar results were found in Chinese patients with fully developed HCC (mean 1.3+/-0.7 microg/L) compared with Chinese healthy controls (mean 0.4+/-0.2 microg/L).


CONCLUSIONS
In conclusion, our data thus proposed an increased suitability of these patient groups for therapeutic approaches with drugs inducing PPARgamma expression, such as methylxanthine derivates.
Gressner
Olav A
OA
Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University Hospital, Aachen, Germany. ogressner@ukaachen.de
Gao
Chunfang
C
Rehbein
Katharina
K
Lahme
Birgit
B
Siluschek
Monika
M
Berg
Thomas
T
Müller
Tobias
T
Gressner
Axel M
AM
D000328:Adult; D000368:Aged; D044466:Asian People; D002110:Caffeine / Q000494:pharmacology; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D044465:White People
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C526317:CCN2 protein, human; D047495:PPAR gamma; D055513:Connective Tissue Growth Factor; D002110:Caffeine; D015230:Prostaglandin D2