Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism.

Gracia-Sancho, Jordi; Manicardi, Nicolò; Ortega-Ribera, Martí; Maeso-Díaz, Raquel; Guixé Muntet, Sergi; Fernández-Iglesias, Anabel; Hide, Diana; García-Calderó, Héctor; Boyer-Díaz, Zoe; Contreras, Patricia C; Spada, Alfred; Bosch, Jaime (2019). Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism. Hepatology communications, 3(7), pp. 987-1000. 10.1002/hep4.1360

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In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De-regulated inflammatory and pro-apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan-caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease. We investigated the effects of 7-day emricasan on hepatic and systemic hemodynamics, liver function, hepatic microcirculatory function, inflammation, fibrosis, hepatic cells phenotype, and paracrine interactions in rats with advanced cirrhosis due to chronic CCl4 administration. The hepato-protective effects of emricasan were additionally investigated in cells isolated from human cirrhotic livers. Cirrhotic rats receiving emricasan showed significantly lower portal pressure than vehicle-treated animals with no changes in portal blood flow, indicating improved vascular resistance. Hemodynamic improvement was associated with significantly better liver function, reduced hepatic inflammation, improved phenotype of hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells and macrophages, and reduced fibrosis. In vitro experiments demonstrated that emricasan exerted its benefits directly improving hepatocytes' expression of specific markers and synthetic capacity, and ameliorated nonparenchymal cells through a paracrine mechanism mediated by small extracellular vesicles released by hepatocytes. Conclusion: This study demonstrates that emricasan improves liver sinusoidal microvascular dysfunction in cirrhosis, which leads to marked amelioration in fibrosis, portal hypertension and liver function, and therefore encourages its clinical evaluation in the treatment of advanced chronic liver disease.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Gracia Sancho, Jorge Sergio; Guixé Muntet, Sergi and Bosch, Jaime

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2471-254X

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

16 Jan 2020 16:24

Last Modified:

16 Jan 2020 16:24

Publisher DOI:

10.1002/hep4.1360

PubMed ID:

31304452

BORIS DOI:

10.7892/boris.137289

URI:

https://boris.unibe.ch/id/eprint/137289

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