Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH

Mar Gil,Maria Teresa Salcedo,Joan Genescà,María Martell,Diana Hide,Imma Raurell,Miren Bravo,Aurora Barberá,Salvador Augustin,Anabel Fernández-Iglesias

doi:10.1038/s41598-019-56366-2

Abstract

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−1·day−1), atorvastatin (ato) (10 mg·kg−1·day−1) 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.

Highlights

The drastic increase in obesity prevalence due to lifestyle changes is bringing on a chronic liver disease epidemic, non-alcoholic fatty liver disease (NAFLD)
NAFLD is considered the hepatic component of the metabolic syndrome covering a broad spectrum of liver damage ranging from simple steatosis, which might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma[1]
We demonstrated that statins exert a general improvement in NASH pathophysiology, including histopathology, portal pressure (PP), endothelial dysfunction, and liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) phenotypes

Summary

Introduction

The drastic increase in obesity prevalence due to lifestyle changes is bringing on a chronic liver disease epidemic, non-alcoholic fatty liver disease (NAFLD). Differentiated liver sinusoidal endothelial cells (LSEC) are characterized by the presence of fenestrae and absence of a basement membrane, allowing a direct communication between sinusoidal blood and the subendothelial space of Disse[9,10,11,12]. This highly specialized phenotype includes CD32b surface antigen expression, which is correlated with the presence of fenestrations[13]. LSEC lose this distinctive properties together with a modification of surface markers expression including loss of CD32b14–16 This dedifferentiation towards a common vascular endothelial phenotype, known as “capillarization”, precedes liver fibrosis and HSC activation in various liver diseases, including NAFLD14,17–19. We provided information regarding sinusoidal endothelial protective effects exerted by statins capable of improving fatty liver disease pathophysiology

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