Abstract
Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor beta (TGF beta). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of ...
Abstract
Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor beta (TGF beta). Recently we have shown that the hepatoprotective adipokine adiponectin downregulates CTGF in primary human hepatocytes (PHH). In the current study, the mechanisms mediating suppression of CTGF by adiponectin and the well described downstream effector of adiponectin receptor 2 (AdipoR2), peroxisome proliferator activated receptor alpha (PPAR alpha), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PH H) and suppression was blocked by a PPAR alpha antagonist indicating that AdipoR2 is involved. The PPAR alpha agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGF beta-mediated upregulation of CTGF. Phosphorylation of the TGF beta downstream effectors SMAD2 and -3 was reduced in PHH incubated with adiponectin or PPAR alpha agonists suggesting that early steps in TGF beta signal transduction are impaired. CTGF and TGF beta mRNA levels were increased in human non-fibrotic non-alcoholic steatohepatitis (NASH), and here AdipoR2 expression was significantly reduced. Current data show that CTGF and TGF beta are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGF beta signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF. (C) 2011 Elsevier Inc. All rights reserved.
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