The mechanism through which octreotide inhibits hepatic stellate cell activity

Abstract

Hepatic stellate cells (HSCs) are important in the development of liver fibrosis and in the pathogenesis of portal hypertension. Octreotide, an analogue of somatostatin, has been demonstrated to effectively treat fibrosis and portal hypertension; however, its relative mechanism in HSCs remains unknown. LX‑2, the immortalized HSC line, was used to study the mechanism whereby octreotide functions at different concentrations. Real‑time polymerase chain reaction (PCR) and western blot analysis were used to analyze the expression of fibrosis markers and transcription factors following treatment with octreotide. Soluble secreted endothelin‑1 (ET‑1), collagen I and vascular endothelial growth factor (VEGF) were assessed in the supernatants of cultured cells by enzyme-linked immunosorbent assay (ELISA). In the present study, it was shown that octreotide was able to inhibit the proliferative ability of the LX‑2 cells and decrease the expression of transforming growth factor β (TGF‑β), α‑smooth muscle actin (α‑SMA) and smad‑4a. The transcription factors, including c‑Jun and sp‑1, were downregulated in a dose‑dependent manner following treatment with octreotide. The levels of ET‑1 and collagen I in the supernatant decreased significantly in contrast with the normal levels, whereas the levels of VEGF in the LX‑2 cells and the supernatant increased at a high octreotide concentration (10‑5 nM). Octreotide may exert its effects on ET‑1 or other targeting genes in HSCs through the downregulation of c‑Jun and specificity protein 1 (sp‑1), and the increased levels of VEGF may be the reason for the side effects observed at high concentrations of octreotide.

Protective role of cortistatin in pulmonary inflammation and fibrosis

“…Again, this effect could be mediated in a paracrine fashion, since fibroblasts express both cortistatin and its receptors (this study, Borie et al, 2008;Egger et al, 2014;Tug et al, 2013), and here we observed that exogenously added cortistatin inhibited directly the expression of several mediators and markers of fibrosis by TGFβ1-activated fibroblasts. In agreement, various studies reported the effect of cortistatin in MAPKs and Akt in other cell types (Duran-Prado et al, 2013;Morell et al, 2014), and other sstr-agonists regulate the activation of fibroblasts (Borie et al, 2008;Wang et al, 2013). Moreover, by using specific antagonists, we provide the evidence that sstr and GHSR play major roles in the anti-fibrotic effects of cortistatin in the lung.…”

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

“…Somatostatin and its analogues are known to curb HSC activation [15] and have been seen to attenuate liver fibrosis/fibrogenesis in other forms of liver injury [42][43][44]. Reynaert and colleagues demonstrated that somatostatin administration reduced both gene and protein expression of α-SMA and collagens I and III by HSCs in vitro [45].…”

SP1 and UTE1 Decoy ODNs inhibit activation and proliferation of hepatic stellate cells by targeting tissue inhibitors of metalloproteinase 1

“…It is well known that over deposition of ECM can impair the liver function and collagen is the main component of ECM produced by activited HSCs [ 20 ]. In activated HSCs, down-regulation of SP1 is able to inhibit the proliferation and the expression of TGF-β, α-SMA and Smad4 [ 21 ]. In human hypertrophic scar fibroblasts, SP1 Decoy ODN can significantly reduce the secretion of collagen [ 22 ].…”