Somatostatin at nanomolar concentration reduces collagen I and III synthesis by but not proliferation of activated rat hepatic stellate cells

摘要

class="enumerated" style="list-style-type:decimal">Previous studies have shown antifibrotic effects of somatostatin. Since hepatic stellate cells (HSC) express somatostatin receptors and play a key role in hepatic fibrogenesis, we investigated the in vitro antifibrotic effect of somatostatin on rat HSC.At day 12 after isolation, cells were exposed to different concentrations of somatostatin (10⁻⁶–10⁻⁹ mol l⁻¹).mRNA expression of collagen types I and III, and of smooth muscle α-actin (α-SMA) was analysed by Northern blotting. At 10⁻⁹ mol l⁻¹, somatostatin significantly reduced mRNA expression of collagen I (72.3±10.7%; 95% confidence interval (95% CI): 45.5–99.0), collagen III (79.0±4.5%; 95% CI: 67.6–90.4) and α-SMA (65.7±5.9%; 95% CI: 51.1–80.2), as compared to control normalized at 100%. These results were confirmed by quantitative RT–PCR.Cycloheximide experiments indicated that somatostatin has no direct transcriptional effect.Using immunoprecipitation, we demonstrated that somatostatin also decreased de novo synthesis of collagen I (73±10%; 95% CI: 48–98%), collagen III (65±13%; 95% CI: 33–97%) and α-SMA (47±9%; 95% CI: 25–69%). Remarkably, at higher concentrations, somatostatin did not suppress collagen mRNA expression nor de novo protein synthesis. We ascribe this observation to desensitization of the cells for somatostatin.Cell proliferation, as measured by 5-bromo-2′-deoxyuridine labelling, was not altered by somatostatin.No significant effect on the intermediate and actin cytoskeleton were detected by immunohistochemistry and Western blotting.Our findings imply that in vivo antifibrotic effects of somatostatin could result partially from a direct action of somatostatin on HSC, but other, in vivo effects are probably also involved.