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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\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>), atorvastatin (ato) (10\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) 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\u2009\u00b1\u20090.37\u2009mmHg <jats:italic>vs<\/jats:italic> 8.30\u2009\u00b1\u20090.22\u2009mmHg; p\u2009&lt;\u20090.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b<jats:sup>\u2212<\/jats:sup>\/CD11b<jats:sup>\u2212<\/jats:sup>) LSEC (8% <jats:italic>vs<\/jats:italic> 1%, p\u2009=\u20090.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29\u2009\u00b1\u20090.25\u2009mmHg, p\u2009&lt;\u20090.01; ato: 8.85\u2009\u00b1\u20090.30\u2009mmHg, p\u2009&lt;\u20090.001), 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.<\/jats:p>","DOI":"10.1038\/s41598-019-56366-2","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T11:02:42Z","timestamp":1577444562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-9125","authenticated-orcid":false,"given":"Miren","family":"Bravo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imma","family":"Raurell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Hide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-6675","authenticated-orcid":false,"given":"Anabel","family":"Fern\u00e1ndez-Iglesias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Barber\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Salcedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Augustin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-8422","authenticated-orcid":false,"given":"Joan","family":"Genesc\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0935-0029","authenticated-orcid":false,"given":"Mar\u00eda","family":"Martell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,27]]},"reference":[{"key":"56366_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/nu9040387","volume":"9","author":"H Kitade","year":"2017","unstructured":"Kitade, H., Chen, G., Ni, Y. & Ota, T. 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