학술논문
The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation.
Document Type
Academic Journal
Author
Martini A; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Turato C; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Cannito S; Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.; Quarta S; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Biasiolo A; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Ruvoletto M; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Novo E; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Marafatto F; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Guerra P; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Tonon M; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Clemente N; Department of Health Science, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.; Bocca C; Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.; Piano SS; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Guido M; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Gregori D; Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Padova, Italy.; Parola M; Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.; Angeli P; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; Pontisso P; Unit of Internal Medicine and Hepatology, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.; European Reference Network - ERN RARE-LIVER, Department of Medicine, Azienda Ospedaliera-Università, Padova, Italy.
Source
Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 8707234 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2036 (Electronic) Linking ISSN: 02692813 NLM ISO Abbreviation: Aliment Pharmacol Ther Subsets: MEDLINE
Subject
Language
English
Abstract
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.
(© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)
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.
(© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)