Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes

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• 作者：Josef Wanninger^a ; Markus Neumeier^a ; Claus Hellerbrand^a ; Doris Schacherer^a ; Sabrina Bauer^a ; Thomas S. Weiss^b ; Hanna Huber^a ; Andreas Sch&#xe4 ; ffler^a ; Charalampos Aslanidis^c ; Jü ; rgen Schö ; lmerich^a ; Christa Buechler^a ; ^{christa.buechler@klinik.uni-regensburg.de"" rel=""nofollow}
• 关键词：Lipid accumulation ; Hepatocyte ; Activin A ; Adiponectin
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2011
• 出版时间：October 2011
• 年：2011
• 卷：1811
• 期：10
• 页码：626-633
• 全文大小：781 K

文摘

Fatty liver is commonly detected in obesity and has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of liver diseases. Transforming growth factor beta (TGFb2;) and activin A, both members of the TGFb2; superfamiliy, are central regulators in liver fibrosis and regeneration, and the effect of hepatocyte lipid accumulation on the release of these proteins was studied. Primary human hepatocytes (PHH) were incubated with palmitic acid or oleic acid to increase lipid storage. Whereas activin A and its natural inhibitor follistatin were not affected, TGFb2; was 2-fold increased. The hepatoprotective adipokine adiponectin dose-dependently induced activin A while lowering follistatin but did not alter TGFb2;. Activin A was markedly reduced in hepatocyte cell lines compared to PHH and was not induced upon adiponectin incubation demonstrating significant differences of primary and transformed cells. In free fatty acid (FFA)-incubated PHH adiponectin-mediated induction of activin A was impaired. Inhibition of TGFb2; receptors ALK4/5 and blockage of SMAD3 phosphorylation rescued activin A synthesis in FFA and in TGFb2; incubated cells suggesting that FFA inhibit adiponectin activity by inducing TGFb2;. To evaluate whether serum levels of activin A and its antagonist are altered in patients with hepatic steatosis, both proteins were measured in the serum of patients with sonographically diagnosed fatty liver and age- and BMI-matched controls. Systemic adiponectin was significantly reduced in patients with fatty liver but activin A and follistatin were not altered. In summary the current data demonstrate that lipid accumulation in hepatocytes induces TGFb2; which impairs adiponectin bioactivity, and thereby may contribute to liver injury.