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
cause of morbidity and mortality worldwide. Identification of
susceptibility/prognosis factors and new therapeutic tools for treating
hepatic fibrotic disorders of various etiologies 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. Here, we
evaluated the capacity of cortistatin to regulate liver fibrosis. We
initially found that 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 to
hepatotoxic and cholestatic injury. Compared to 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. In conclusion, we identify cortistatin as an endogenous
molecular break of liver fibrosis and its deficiency as a potential
poor-prognosis marker for chronic hepatic disorders that course with
fibrosis. Cortistatin-based therapies emerge as attractive strategies
for ameliorating severe hepatic fibrosis.