Cortistatin regulates fibrosis and myofibroblast activation in experimental hepatotoxic- and cholestatic-induced liver injury

Abstract

Background and purpose: Liver fibrosis induced by chronic hepatic injury remains a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis.

Experimental approach: We experimentally induced liver fibrosis in mice by chronic CCl₄ exposure and bile duct ligation and evaluated the histopathological signs and fibrotic markers.

Key results: Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged by hepatotoxic and cholestatic injury. Compared with wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury.

Conclusion and implications: We identify cortistatin as an endogenous molecular brake on liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that link with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various aetiologies.

Keywords: Kupffer cells; bile duct ligation; contractile fibres; hepatic stellate cell; neuropeptide; periportal fibroblast.