Cytosolic phospholipase A2α and peroxisome proliferator-activated receptor γ signaling pathway counteracts transforming growth factor β–mediated inhibition of primary and transformed hepatocyte growth

✍ Scribed by Chang Han; William C. Bowen; Guiying Li; Anthony J. Demetris; George K. Michalopoulos; Tong Wu

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 735 KB
• Volume: 52
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.23703

✦ Synopsis

Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor b (TGFb) 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-b influences hepatic cell functions remain incompletely defined. We report herein that TGF-b regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cytosolic phospholipase A 2 a (cPLA 2 a), a rate-limiting key enzyme that releases arachidonic acid for the production of bioactive eicosanoids. The interplays between TGFb and cPLA 2 a signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells, and hepatocytes isolated from newly developed cPLA 2 a transgenic mice. Conclusion: Our data show that cPLA 2 a activates peroxisome proliferatoractivated receptor c (PPAR-c) and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-b signaling by cPLA 2 a and PPAR-c may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis.