title: Adiponectin reduces connective tissue growth factor in human hepatocytes which is already induced in non-fibrotic non-alcoholic steatohepatitis.
abstract: Connective tissue growth factor (CTGF) is induced in liver fibrosis and enhances the activity of transforming growth factor β (TGFβ). 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 α (PPARα), were analyzed in more detail. Adiponectin downregulated CTGF mRNA and protein in primary human hepatocytes (PHH) and suppression was blocked by a PPARα antagonist indicating that AdipoR2 is involved. The PPARα agonists fenofibrate and WY14643 also reduced CTGF protein in these cells. Adiponectin further impaired TGFβ-mediated upregulation of CTGF. Phosphorylation of the TGFβ downstream effectors SMAD2 and -3 was reduced in PHH incubated with adiponectin or PPARα agonists suggesting that early steps in TGFβ signal transduction are impaired. CTGF and TGFβ 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 TGFβ are already induced in non-fibrotic NASH and this may be partly explained by low adiponectin bioactivity which interferes with TGFβ signaling by reducing phosphorylation of SMAD2/3 and by downregulating CTGF.
authors.affiliation: Department of Internal Medicine I, University Hospital of Regensburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Walter
authors.forename: Josef
authors.initials: J
authors.lastname: Wanninger
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bauer
authors.forename: Kristina
authors.initials: K
authors.lastname: Eisinger
authors.forename: Markus
authors.initials: M
authors.lastname: Neumeier
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Thomas
authors.initials: T
authors.lastname: Amann
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäffler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schölmerich
authors.forename: Christa
authors.initials: C
authors.lastname: Buechler
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D047493:PPAR alpha / Q000819:agonists; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000924:Anticholesteremic Agents; D047493:PPAR alpha; D011743:Pyrimidines; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; C006253:pirinixic acid; D011345:Fenofibrate