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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

ABSTRACT: Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

SUBMITTER: Drzewiecki K

PROVIDER: S-EPMC8105721 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

Drzewiecki Kaela K Choi Jungmin J Brancale Joseph J Leney-Greene Michael A MA Sari Sinan S Dalgiç Buket B Ünlüsoy Aksu Aysel A Evirgen Şahin Gülseren G Ozen Ahmet A Baris Safa S Karakoc-Aydiner Elif E Jain Dhanpat D Kleiner David D Schmalz Michael M Radhakrishnan Kadakkal K Zhang Junhui J Hoebe Kasper K Su Helen C HC Pereira João P JP Lenardo Michael J MJ Lifton Richard P RP Vilarinho Sílvia S

The Journal of experimental medicine 20210506 7

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in ...[more]

PMID: 33956074

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Project description:Background & aimsPortal hypertension (PH) is a frequent and severe clinical syndrome associated with chronic liver disease. Considering the mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesised that PH might influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of increased hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH.MethodsPrimary 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. RNA sequencing was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of patients with chronic liver disease with PH (n = 73) and participants without PH (n = 23). Biomarker discovery was performed in two additional independent cohorts of 104 patients with PH and 18 patients without PH.ResultsTranscriptomic analysis revealed 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 hepatic venous pressure gradient. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Two downstream targets inhibited by CBX7, namely, E-cadherin (ECAD) and serine protease inhibitor Kazal-type 1 (SPINK1), were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH.ConclusionsWe characterise the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose the combination of two of its reported products as biomarkers of PH.Impact and implicationsIncreased pressure in the portal venous system that typically occurs during chronic liver disease (called portal hypertension) is one of the main drivers of related clinical complications, which are linked to a higher risk of death. In this study, we found that pathological pressure has a harmful effect on liver sinusoidal endothelial cells and identified CBX7 as a key protein involved in this process. CBX7 regulates the expression of E-cadherin and SPINK1, and consequently, measuring these proteins in the blood of patients with chronic liver disease allows the prediction of portal hypertension and clinically significant portal hypertension.

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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

Publications

GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

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