Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH
Bravo, Miren (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Raurell, Imma (Vall d'Hebron Institut de Recerca (VHIR))
Hide, Diana (Vall d'Hebron Institut de Recerca (VHIR))
Fernández-Iglesias, Anabel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Gil, Mar (Vall d'Hebron Institut de Recerca (VHIR))
Barberá Bellés, Aurora (Vall d'Hebron Institut de Recerca (VHIR))
Salcedo, Maria-Teresa (Hospital Universitari Vall d'Hebron)
Augustin Recio, Salvador (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Genescà Ferrer, Joan (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Martell, María (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg·day), atorvastatin (ato) (10 mg·kg·day) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10. 47 ± 0. 37 mmHg vs 8. 30 ± 0. 22 mmHg; p < 0. 001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b/CD11b) LSEC (8% vs 1%, p = 0. 005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9. 29 ± 0. 25 mmHg, p < 0. 01; ato: 8. 85 ± 0. 30 mmHg, p < 0. 001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.
Ajuts:	Instituto de Salud Carlos III PI18-00947 Instituto de Salud Carlos III PI17-00310 Instituto de Salud Carlos III PI17-00754 Instituto de Salud Carlos III PI15-00066
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Scientific reports, Vol. 9 Núm. 1 (january 2019) , p. 20183, ISSN 2045-2322

DOI: 10.1038/s41598-019-56366-2
PMID: 31882668

12 p, 5.8 MB

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