ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P496

Lipid-loaded hepatocytes release soluble factors that activate hepatic stellate cells: a new in vitro model to study fibrogenesis in NASH

Hella Wobser, Christoph Dorn, Thomas Weiss, Jürgen Schölmerich & Claus Hellerbrand

University Clinic, Regensburg, Germany.

Background: Non-alcoholic steatohepatitis (NASH) can progress to hepatic fibrosis and end-stage liver disease. Hepatic stellate cells (HSC) are the central mediators of liver fibrosis. The molecular mechanisms linking hepatic steatosis to activation of HSC, thereby promoting inflammation and fibrosis, are mainly unknown. Here, we demonstrate a novel in vitro model to study the effect of hepatic lipid accumulation on HSC.

Methods and results: After exposure of human hepatocytes to the saturated fatty acid palmitate (PA), significant intracellular lipid accumulation was documented morphologically and by colorimetric assays. Subsequently, conditioned-media (CM) from PA-treated hepatocytes were used for stimulation of HSC, leading to enhanced proliferation and induction of the activation process of HSC. Furthermore, CM from PA-treated cells significantly induced a pro-inflammatory (MCP-1) and fibrogenic gene expression (Collagen I, TGF-beta, TIMP-1/-2, MMP-2) in HSC. Flow cytometric analysis revealed a significant apoptosis resistance of HSC after stimulation with CM from steatotic hepatocytes.

Summary and conclusion: Lipid accumulation in hepatocytes causes the secretion of soluble mediators that stimulate activation and proliferation of HSC as well as the expression of pro-inflammatory and fibrogenic genes in HSC. These findings demonstrate a potential mechanism how hepatic steatosis contributes to the progression of inflammation and fibrosis in NAFLD. Furthermore, this study provides an attractive in vitro model to identify innovative anti-fibrotic strategies for the therapy of NAFLD/NASH.

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