Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

• Published in: Scientific reports 2017-06, Vol.7 (1), p.3255-10, Article 3255
• Main Authors: de Mesquita, Fernanda Cristina, Guixé-Muntet, Sergi, Fernández-Iglesias, Anabel, Maeso-Díaz, Raquel, Vila, Sergi, Hide, Diana, Ortega-Ribera, Martí, Rosa, José Luís, García-Pagán, Juan Carlos, Bosch, Jaime, de Oliveira, Jarbas Rodrigues, Gracia-Sancho, Jordi
• Format: Article
• Language: English
• Subjects: 13/106; 14/1; 14/19; 38/77; 692/4020/4021/1607/1560; 692/4020/4021/288; 82/80; 96/106; Animal models; Animals; Antidiabetics; Cell proliferation; Cell Proliferation - drug effects; Cirrhosis; Cirrosi hepàtica; Diabetes mellitus; Disease Models, Animal; Fibrosis; Genotype & phenotype; Hepatic cirrhosis; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Humanities and Social Sciences; Humans; Incretins - pharmacology; Inflammation; Liraglutide - pharmacology; Liver; Liver - blood supply; Liver cirrhosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - physiopathology; Liver diseases; Malalties del fetge; Male; Microvasculature; Microvessels - drug effects; Molecular modelling; multidisciplinary; NF-κB protein; Oxidizing agents; Rats, Wistar; Rodents; Science; Science (multidisciplinary); Sox9 protein; Stellate cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-02866-y

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.