Antifibrotic effects of adiponectin include induction of BMP-activated and membrane bound inhibitor (Bambi) in liver cells which antagonizes TGF-beta activity

Objectives: TGF-beta induces activation of hepatic stellate cells and an epithelial mesenchymal transition of hepatocytes, and thereby promotes the progression of liver fibrosis. BMP-activated and membrane bound inhibitor (Bambi) mimics TGF-beta receptor I, but lacks an intracellular kinase domain and interaction of Bambi with TGF-beta receptor II results in a non functional TGF-beta pseudoreceptor. Adiponectin, whose systemic levels are reduced in patients with non-alcoholic fatty liver disease, protects from liver fibrosis, and it was analysed whether this adipokine induces Bambi in human liver cells. Methods: Real-time RT-PCR and immunoblot were performed using primary human hepatocytes, hepatic stellate cells and liver tissues of patients with and without liver steatosis. Human liver tissue for immunoblot analysis and cell isolation was obtained according to the guidelines of the charitable state-controlled foundation Human Tissue & Cell Research (HTCR) with the patient's informed consent. Results: Bambi protein was found reduced in whole liver lysates of human fatty liver compared to non-steatotic liver. Adiponectin induced Bambi in primary human hepatocytes (PHH) and hepatic stellate cells in vitro. Specific antagonists were used to show that the upregulation of Bambi in PHH is driven via NF-kappaB and ERK1/2 signalling pathways. Preincubation with adiponectin lowered phosphorylation of Smad 2 and Smad 3 in hepatocytes upon TGF-beta incubation. Overexpression of Bambi in HepG2 cells significantly impaired TGF-beta mediated induction of connective tissue growth factor (CTGF). Conclusion: Adiponectin impairs TGF-beta activity in hepatocytes partly by induction of Bambi protein. Low levels of Bambi in human fatty liver may contribute to enhanced TGF-beta signalling and progression of fibrosis. The antifibrogenic effects of adiponectin make this adipokine an interesting therapeutic target in non-alcoholic fatty liver disease.

Liver fibrosis - adiponectin - hepatocyte