The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation
© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd..
BACKGROUND: SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function.
AIMS: To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro.
METHODS: We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins.
RESULTS: Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-β1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-β1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein.
CONCLUSIONS: The polymorphic variant SB3-PD is highly effective in determining activation of TGF-β1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
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| Enthalten in: |
Alimentary pharmacology & therapeutics - 59(2024), 3 vom: 01. Jan., Seite 380-392 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Martini, Andrea [VerfasserIn] |
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| Links: |
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| Themen: |
Fibrosis |
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| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 12.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/apt.17804 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364817704 |
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| 520 | |a © 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. | ||
| 520 | |a BACKGROUND: SerpinB3 is a cysteine protease inhibitor involved in liver disease progression due to its proinflammatory and profibrogenic properties. The polymorphic variant SerpinB3-PD (SB3-PD), presents a substitution in its reactive centre loop, determining the gain of function | ||
| 520 | |a AIMS: To disclose the clinical characteristics of a cohort of patients with cirrhosis in relation to the presence of SB3-PD and to assess the effect of this genetic variant on fibrogenic and inflammatory cytokines in vitro | ||
| 520 | |a METHODS: We assessed SB3 polymorphism in 90 patients with cirrhosis, prospectively followed up in our referral centre. We used HepG2 and HuH-7 cells transfected to overexpress either wild-type SB3 (SB3-WT) or SB3-PD to assess their endogenous effect, while LX2 and THP-1 cells were treated with exogenous SB3-WT or SB3-PD proteins | ||
| 520 | |a RESULTS: Patients carrying SB3-PD had more severe portal hypertension and higher MELD scores, than patients carrying SB3-WT. In multivariate analysis, SB3-PD was an independent predictor of cirrhosis complications. Patients with SB3-PD polymorphism presented with more severe liver fibrosis and inflammatory features. Hepatoma cells overexpressing SB3-PD showed higher TGF-β1 expression than controls. The addition of recombinant SB3-PD induced an up-regulation of TGF-β1 in LX2 cells and a more prominent inflammatory profile in THP-1 cells, compared to the effect of SB3-WT protein | ||
| 520 | |a CONCLUSIONS: The polymorphic variant SB3-PD is highly effective in determining activation of TGF-β1 and inflammation in vitro. Patients with cirrhosis who carry SB3-PD polymorphism may be more prone to develop severe liver disease progression. However, further validation studies are warranted to support the in vivo relevance of this polymorphism | ||
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