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Aging and disease    2019, Vol. 10 Issue (4) : 684-698     DOI: 10.14336/AD.2019.0127
Orginal Article |
Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease
Raquel Maeso-Díaz1, Martí Ortega-Ribera1, Erica Lafoz1, Juan José Lozano2, Anna Baiges1,2, Rubén Francés2,3, Agustín Albillos2,4, Carmen Peralta2,5, Juan Carlos García-Pagán1,2, Jaime Bosch1,2,6, Victoria C Cogger7, Jordi Gracia-Sancho1,2,6,*
1Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, University of Barcelona Medical School, Barcelona, Spain
2Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), Madrid, Spain
3Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL -Fundación FISABIO), Alicante, Spain
4 Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain
5Protective Strategies Against Hepatic Ischemia-Reperfusion Group, IDIBAPS, Barcelona, Spain
6Hepatology, Department of Biomedical Research, Inselspital, Bern University, Switzerland
7Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia
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Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.

Keywords Cirrhosis      portal hypertension      hepatic sinusoid      elderly      liver microcirculation     
Corresponding Authors: Gracia-Sancho Jordi   
About author:

These authors contributed equally to this study.

Just Accepted Date: 18 February 2019   Issue Date: 01 August 2019
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Raquel Maeso-Díaz
Martí Ortega-Ribera
Erica Lafoz
Juan José Lozano
Anna Baiges
Rubén Francés
Agustín Albillos
Carmen Peralta
Juan Carlos García-Pagán
Jaime Bosch
Victoria C Cogger
Jordi Gracia-Sancho
Cite this article:   
Raquel Maeso-Díaz,Martí Ortega-Ribera,Erica Lafoz, et al. Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease[J]. Aging and disease, 2019, 10(4): 684-698.
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4 m.o.
20 m.o.
% changep-value
Body weight (g)371 ± 16701 ± 35+88<0.001
Liver (g)10.7 ± 0.617.9 ± 0.9+67<0.001
Liver-body weight ratio (%)2.88 ± 0.132.57 ± 0.14-110.09
AST (U/L)189 ± 11304 ± 47+610.03
ALT (U/L)82 ± 897 ± 8+200.17
Bilirubin (mg/dL)0.51 ± 0.240.51 ± 0.120>0.20
Bile production (µL/min*g)30 ± 818 ± 3-400.16
Albumin (mg/dL)26 ± 120 ± 2-240.01
Plasma cholesterol (mg/dL)75 ± 5106 ± 11+410.01
Plasma LDL cholesterol (mg/dL)45 ± 475 ± 8+660.007
Plasma HDL cholesterol (mg/dL)20 ± 213 ± 2-330.03
Plasma triglycerides (mg/dL)41 ± 884 ± 13+1070.01
Plasma FFA (mg/dL)623 ± 67504 ± 70-19>0.20
Oil red O-staining (%)0.47 ± 0.141.83 ± 0.32+2890.04
MDA (nmol/mg protein)2.68 ± 0.682.36 ± 0.28-12>0.20
LPS (EU/mL)1.13 ± 0.192.00 ± 0.13+770.002

PP (mmHg)14.3 ± 0.316.9 ± 1.2+180.03
PBF (mL/min*g)1.21 ± 0.121.59 ± 0.23+310.12
HVR (mmHg*min/mL*g)12.7 ± 1.412.5 ± 2.3-2>0.20
Ex vivo HVR (mmHg*min/mL*g)0.23 ± 0.030.41 ± 0.04+780.002
MAP (mmHg)91 ± 6103 ± 7+13>0.20
HR (bpm)340 ± 15338 ± 16-0.5>0.20
Table 1  Biometric, biochemical and hemodynamic characteristics in aCLD-young and aCLD-old rats.
Figure 1.  Hepatocyte phenotype markers in 4 months-young and 20 months-old rats with aCLD

(A) Representative transmission electron microscopy images and corresponding quantification of numbers of sinusoids (S), lack of microvilli (M), big space of Disse (D), peliosis(P), basal lamina deposition and number of necrotic hepatocytes (H) in liver tissue from 4 months-young and 20 months-old rats with aCLD. (B) HNF4α, Oct1, Mrp2 and Mrp3 mRNA expression in livers described in A. n=3 (A) and (B) n=7 per group. Results represent mean ± S.E.M. All images: 3000X, scale bar=20μm.

Figure 2.  LSEC phenotype markers in aged rats with aCLD

The following markers of sinusoidal endothelial phenotype were analysed in liver tissue from 4 months-young and 20 months-aged rats with aCLD. (A) mRNA expression of KLF2 and CD32b. (B) Representative images of CD32b immunehistochemistry and corresponding quantification. (C) Representative images of eNOS immunohistochemistry and corresponding quantification. (D) Representative images of vWF immunohistochemistry and corresponding quantification. (E) mRNA expression of HGF, Wnt2, Hamp and Axin2. (F) Representative scanning electron microscopy images & quantification of porosity, fenestration frequency and fenestration diameter. n=7 (A-E) and n=3 (F) per group. Results represent mean ± S.E.M. Images from B-D: 400X, scale bar=50μm. Images from F: 15000X, scale bar=1μm.

Figure 3.  Aging increases fibrotic deposition, HSC activation and macrophages infiltration

Fibrotic content, HSC phenotype and macrophage infiltration and phenotype were evaluated in young and aged rats with aCLD. (A) Representative images of fibrotic content measured as positive area for Sirius Red with their corresponding quantifications. (B) Representative western blot of Collagen I normalized to GAPDH. (C) Representative western blot of α-SMA normalized to GAPDH. (D) Representative western blots of moesin and p-moesin and corresponding quantification. (E) Left, representative images of CD68 immunofluorescence in liver tissue and corresponding quantification. Right, representative images of CD163 immunohistochemistry in liver tissue and its quantification. (F) Expression of TNF-α, iNOS, and IL-6 as pro-inflammatory markers (left) and Mrc1, Arg1 and IL-10 as anti-inflammatory markers (right) in liver tissue from young and old rats with aCLD. n=7 per group. Results represent mean ± S.E.M. All images: 400X, scale bar=50μm.

Figure 4.  Aged-related changes in the gene signature of cirrhotic human liver

Gene expression analysis in cirrhotic young and old human livers. (A) Left, fold enrichments (log2) are plotted in a heatmap using red colour for transcripts that are increased or using green colour for transcripts that are decreased in old cirrhotic humans. Right, pathway enrichment analysis results for genes upregulated (red) and downregulated (green) are summarized. (B) Representative gene sets upregulated (red) or downregulated (green) related to microcirculatory function in old cirrhotic humans, full description of top ten gene sets can be found in supplementary materials. FDR < 10%, n=7 per group. Clinical characteristics of donors are described in Supplementary table 1.

Figure 5.  Effects of simvastatin on hepatocytes and microcirculatory function

(A) HNF4α, Oct1, Mrp2 and Mrp3 mRNA expression in livers from aged rats with aCLD treated with simvastatin or vehicle. (B) Cytochrome P4503A4 activity in hepatocytes isolated from livers described in A. (C) Representative transmission electron microscopy images and corresponding quantification of numbers of sinusoids (S), lack of microvilli (M), big space of Disse (D), peliosis and number of necrotic hepatocytes (H). (D) Microvascular function evaluation in livers from aged rats with aCLD treated with simvastatin or vehicle. (E) Representative images of vWF immunohistochemistry and corresponding quantification from livers described in A. (F) Representative scanning electron microscopy images & quantification of porosity, fenestration frequency and fenestration diameter. n=10 (A-B, D-E), n=5 (B) and n=3 (C and F) per group. Results represent mean ± S.E.M. Images from C: 3000X, scale bar=20μm. Images from E: 400X, scale bar=50μm. Images from F: 15000X, scale bar=1μm.

Figure 6.  Simvastatin promotes decreased fibrosis deposition and HSC de-activation

(A) Representative images of fibrotic content, α-SMA and desmin with their corresponding quantifications. (B) α-SMA and Collagen I protein expression in total liver tissue, normalized to GAPDH. (C) Representative western blots of moesin and p-moesin and corresponding quantification. n=10 (A-C). Results represent mean ± S.E.M. All images 400X, scale bar=50μm.

VehicleSimvastatin% changep-value
Body weight (g)655 ± 31681 ± 18+4> 0.20
Liver (g)16.6 ± 1.019.1 ± 1.1+150.15
Liver-body weight ratio (%)2.58 ± 0.192.81 ± 0.15+9> 0.20
AST (U/L)188 ± 34155 ± 28-18> 0.20
ALT (U/L)61 ± 557 ± 6-7> 0.20
CKM (ng/mL)64 ± 1347 ± 10-27> 0.20
Bilirubin (mg/dL)0.23 ± 0.060.10 ± 0.00-570.05
Bile production (µL/min*100g bw)23.5 ± 7.142.0 ± 16.5+450.17
Albumin (mg/dL)22.0 ± 1.124.2 ± 0.8+100.10
Plasma cholesterol (mg/dL)86 ± 579 ± 10-8> 0.20
Plasma LDL cholesterol (mg/dL)64 ± 555 ± 7-14> 0.20
Plasma HDL cholesterol (mg/dL)14.0 ± 1.515.6 ± 2.6+7> 0.20
Plasma triglycerides (mg/dL)38.0 ± 5.142.1 ± 7.1+11> 0.20
Oil red O-staining (%)1.33 ± 0.221.64 ± 0.39+23> 0.20
MDA (nmol/mg protein)2.68 ± 0.742.35 ± 0.30-120.15
LPS (EU/mL)1.49 ± 0.181.62 ± 0.13+8> 0.20

PP (mmHg)15.9 ± 1.411.9 ± 0.8-250.02
PBF (mL/min*g)1.28 ± 0.171.13 ± 0.16-12>0.20
HVR (mmHg*min/mL*g)13.9 ± 2.412.4 ± 1.5-11>0.20
Ex vivo HVR (mmHg*min/mL*g)0.39 ± 0.040.32 ± 0.03-180.20
MAP (mmHg)97 ± 6110 ± 5+13>0.20
HR (bpm)332 ± 22381 ± 25+150.06
Table 2  Biometric, biochemical and hemodynamic characteristics in aCLD-old rats treated with simvastatin or vehicle.
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