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CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY
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  • Raquel Benitez,
  • Marta Caro,
  • Eduardo Andrés-León,
  • Francisco O'Valle,
  • Mario Delgado
Raquel Benitez
Instituto de Parasitologia y Biomedicina Lopez-Neyra
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Marta Caro
Instituto de Parasitologia y Biomedicina Lopez-Neyra
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Eduardo Andrés-León
Bioinformatics Unit, Instituto de Parasitología y Biomedicina “López-Neyra”
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Francisco O'Valle
University ofGranada
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Mario Delgado
Consejo Superior de Investigaciones Cientificas
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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.

Peer review status:IN REVISION

17 Jun 2021Submitted to British Journal of Pharmacology
18 Jun 2021Assigned to Editor
18 Jun 2021Submission Checks Completed
24 Jun 2021Reviewer(s) Assigned
24 Jul 2021Review(s) Completed, Editorial Evaluation Pending
28 Jul 2021Editorial Decision: Revise Minor