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Hepatology. 2010 Aug;52(2):644-55. doi: 10.1002/hep.23703.

Cytosolic phospholipase A2alpha and peroxisome proliferator-activated receptor gamma signaling pathway counteracts transforming growth factor beta-mediated inhibition of primary and transformed hepatocyte growth.

Author information

  • 1Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA. chan@tulane.edu

Abstract

Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor beta (TGF-beta) is a multifunctional cytokine pivotal in the regulation of hepatic cell growth, differentiation, migration, extracellular matrix production, stem cell homeostasis, and hepatocarcinogenesis. However, the mechanisms by which TGF-beta influences hepatic cell functions remain incompletely defined. We report herein that TGF-beta regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a rate-limiting key enzyme that releases arachidonic acid for the production of bioactive eicosanoids. The interplays between TGF-beta and cPLA(2)alpha signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells, and hepatocytes isolated from newly developed cPLA(2)alpha transgenic mice.

CONCLUSION:

Our data show that cPLA(2)alpha activates peroxisome proliferator-activated receptor gamma (PPAR-gamma) and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-beta signaling by cPLA(2)alpha and PPAR-gamma may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis.

PMID:
20683962
[PubMed - indexed for MEDLINE]
PMCID:
PMC3013516
Free PMC Article

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