Elevated Concentrations of 15-deoxy-Delta12,14-prostaglandin J2 in Chronic Liver Disease Propose Therapeutic Trials With Peroxisome Proliferator Activated Receptor Gamma-Inducing Drugs

Liver Int. 2009 May;29(5):730-5. doi: 10.1111/j.1478-3231.2008.01895.x. Epub 2008 Oct 15.

Abstract

Background/aims: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asian Continental Ancestry Group
  • Caffeine / pharmacology
  • Connective Tissue Growth Factor / antagonists & inhibitors*
  • European Continental Ancestry Group
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Male
  • Middle Aged
  • PPAR gamma / metabolism*
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / blood
  • Prostaglandin D2 / metabolism
  • Up-Regulation / drug effects

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • CCN2 protein, human
  • PPAR gamma
  • Connective Tissue Growth Factor
  • Caffeine
  • Prostaglandin D2