The polymorphic variant of SerpinB3 (SerpinB3-PD) is associated with faster cirrhosis decompensation.

Autor: 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.
Jazyk: angličtina
Zdroj: Alimentary pharmacology & therapeutics [Aliment Pharmacol Ther] 2024 Feb; Vol. 59 (3), pp. 380-392. Date of Electronic Publication: 2023 Nov 21.
DOI: 10.1111/apt.17804
Abstrakt: 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.)
Databáze: MEDLINE
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