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

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?-/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?

SUBMITTER: Bravo M

PROVIDER: S-EPMC6934751 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Bravo Miren M Raurell Imma I Hide Diana D Fernández-Iglesias Anabel A Gil Mar M Barberá Aurora A Salcedo Maria Teresa MT Augustin Salvador S Genescà Joan J Martell María M

Scientific reports 20191227 1

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 imp ...[more]

PMID: 31882668

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Project description:Background & aimsMechanical forces contribute to portal hypertension (PHTN) and fibrogenesis. We investigated the mechanisms by which forces are transduced by liver sinusoidal endothelial cells (LSECs) into pressure and matrix changes.MethodsWe isolated primary LSECs from mice and induced mechanical stretch with a Flexcell device, to recapitulate the pulsatile forces induced by congestion, and performed microarray and RNA-sequencing analyses to identify gene expression patterns associated with stretch. We also performed studies with C57BL/6 mice (controls), mice with deletion of neutrophil elastase (NE-/-) or peptidyl arginine deiminase type IV (Pad4-/-) (enzymes that formation of neutrophil extracellular traps [NETs]), and mice with LSEC-specific deletion of Notch1 (Notch1iΔEC). We performed partial ligation of the suprahepatic inferior vena cava (pIVCL) to simulate congestive hepatopathy-induced portal hypertension in mice; some mice were given subcutaneous injections of sivelestat or underwent bile-duct ligation. Portal pressure was measured using a digital blood pressure analyzer and we performed intravital imaging of livers of mice.ResultsExpression of the neutrophil chemoattractant CXCL1 was up-regulated in primary LSECs exposed to mechanical stretch, compared with unexposed cells. Intravital imaging of livers in control mice revealed sinusoidal complexes of neutrophils and platelets and formation of NETs after pIVCL. NE-/- and Pad4-/- mice had lower portal pressure and livers had less fibrin compared with control mice after pIVCL and bile-duct ligation; neutrophil recruitment into sinusoidal lumen of liver might increase portal pressure by promoting sinusoid microthrombi. RNA-sequencing of LSECs identified proteins in mechanosensitive signaling pathways that are altered in response to mechanical stretch, including integrins, Notch1, and calcium signaling pathways. Mechanical stretch of LSECs increased expression of CXCL1 via integrin-dependent activation of transcription factors regulated by Notch and its interaction with the mechanosensitive piezo calcium channel.ConclusionsIn studies of LSECs and knockout mice, we identified mechanosensitive angiocrine signals released by LSECs which promote PHTN by recruiting sinusoidal neutrophils and promoting formation of NETs and microthrombi. Strategies to target these pathways might be developed for treatment of PHTN. RNA-sequencing accession number: GSE119547.

Project description:Abstract: Background and aims: Portal hypertension (PH) is the most frequent and severe clinical syndrome associated to chronic liver disease (CLD), defined by a pathological increase in the hepatic venous pressure gradient (HVPG). Considering the known mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesized that PH could not only be a consequence of, but significantly influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of pathological hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH. Methods: Primary LSECs were cultured under normal or increased hydrodynamic pressure within a pathophysiological range (1 vs 12 mmHg) using a microfluidic liver-on-a-chip device. RNAseq was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of CLD patients with PH (n=73) vs subjects without PH (n=23). Biomarker discovery was performed in plasma from a third independent cohort of 64 patients (46 with PH vs 18 w/o). Results: Transcriptomic analysis revealed a marked deleterious effect of pathological pressure in LSECs and identified chromobox 7 (CBX7) as a key transcription factor diminished by pressure. Hepatic CBX7 downregulation was validated in patients with PH and significantly correlated with HVPG. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Analysis of two downstream targets of CBX7, ECAD and SPINK1, were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH, with a sensitivity of 91.3% and 91.4% respectively. Conclusions: We describe the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose that the combination of two of its reported products could be used as plasma biomarkers of PH.

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

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

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