CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY

Abstract

Liver fibrosis induced by chronic hepatic injury remains as a major\ncause of morbidity and mortality worldwide. Identification of\nsusceptibility/prognosis factors and new therapeutic tools for treating\nhepatic fibrotic disorders of various etiologies are urgent medical\nneeds. Cortistatin is a neuropeptide with potent anti-inflammatory and\nanti-fibrotic activities in lung that binds to receptors that are\nexpressed in liver fibroblasts and hepatic stellate cells. Here, we\nevaluated the capacity of cortistatin to regulate liver fibrosis. We\ninitially found that hepatic expression of cortistatin inversely\ncorrelated with liver fibrosis grade in mice and humans with hepatic\ndisorders. Cortistatin-deficient mice showed exacerbated signs of liver\ndamage and fibrosis and increased mortality rates when challenged to\nhepatotoxic and cholestatic injury. Compared to wild-type mice,\nnon-parenchymal liver cells isolated from cortistatin-deficient mice\nshowed increased presence of cells with activated myofibroblast\nphenotypes and a differential genetic signature that is indicative of\nactivated hepatic stellate cells and periportal fibroblasts and of\nmyofibroblasts with active contractile apparatus. Cortistatin treatment\nreversed in vivo and in vitro these exaggerated fibrogenic phenotypes\nand protected from progression to severe liver fibrosis in response to\nhepatic injury. In conclusion, we identify cortistatin as an endogenous\nmolecular break of liver fibrosis and its deficiency as a potential\npoor-prognosis marker for chronic hepatic disorders that course with\nfibrosis. Cortistatin-based therapies emerge as attractive strategies\nfor ameliorating severe hepatic fibrosis.