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The regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure.

ABSTRACT: Following parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide (NO) regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase, would be reflected in the gene expression profiles in the liver remnant by employing a global porcine cDNA microarray chip with approximately 23 000 genes represented. Six pig livers were resected with 62% (Low Portal Pressure Resection, LPPR) and 75% (High Portal Pressure Resection) resulting in a portal venous pressure increase from a baseline of 6.1 mmHg to 8.2 and 12 mmHg respectively. By sampling consecutive biopsies from the liver remnants we found differentially expressed genes in the HPPR group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the LPPR group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation and development and protein metabolism. Also common to both groups was both up- and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. Conclusions: The genetic regenerative response in the liver remnant to varies according to the level of resection. Keywords: time course, treatment comparison

ORGANISM(S): Sus scrofa

PROVIDER: GSE6860 | GEO | 2008/01/14

SECONDARY ACCESSION(S): PRJNA99105

REPOSITORIES: GEO

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Project description:Following parenchymal loss, the liver regenerates restoring normal mass and metabolic function. Prevailing theories on triggering events leading to regeneration include humoral, metabolic and flow-mediated mechanisms, the latter emphasizing the importance of shear stress mediated nitric oxide (NO) regulation. We aimed to investigate whether the grade of resection and hence the portal venous pressure and sinusoidal shear stress increase, would be reflected in the gene expression profiles in the liver remnant by employing a global porcine cDNA microarray chip with approximately 23 000 genes represented. Six pig livers were resected with 62% (Low Portal Pressure Resection, LPPR) and 75% (High Portal Pressure Resection) resulting in a portal venous pressure increase from a baseline of 6.1 mmHg to 8.2 and 12 mmHg respectively. By sampling consecutive biopsies from the liver remnants we found differentially expressed genes in the HPPR group to have functions related primarily to apoptosis, nitric oxide metabolism and oxidative stress, whereas differentially expressed genes in the LPPR group potentially regulate the cell cycle. Common to both groups was the upregulation of genes regulating inflammation, transport, cell proliferation and development and protein metabolism. Also common to both groups was both up- and downregulation of genes regulating cell-cell signaling, signal transduction, cell adhesion and translation. Genes regulating the metabolism of lipids, hormones, amines, and alcohol were downregulated in both groups. Conclusions: The genetic regenerative response in the liver remnant to varies according to the level of resection. Keywords: time course, treatment comparison Three pigs underwent a 62% liver resection (low-pressure resection, LPR) and three underwent a 75% resection (high-pressure resection, HPR). Biopsies from the liver remnant were taken from all animals at time points 1, 30, 90, minutes and 3, 4 and 6 hours after resection. Expression profiling was conducted by hybridising each sample against a common reference, consisting of liver RNA from an unrelated animal.

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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The regenerative response in the pig liver remnant varies with the degree of resection and rise in portal pressure.

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