SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease.

Autor: Salomone F; Division of Gastroenterology, Ospedale di Acireale, Azienda Sanitaria Provinciale di Catania, Catania, Italy. Electronic address: federicosalomone@rocketmail.com., Pipitone RM; Department PROMISE, University of Palermo, Palermo, Italy., Longo M; Medicine & Metabolic Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy., Malvestiti F; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Amorini AM; Department BIOMETEC, University of Catania, Catania, Italy., Distefano A; Deparment of Clinical and Molecular Medicine, University of Gothenburg, Sweden., Casirati E; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Ciociola E; Deparment of Clinical and Molecular Medicine, University of Gothenburg, Sweden., Iraci N; Department BIOMETEC, University of Catania, Catania, Italy., Leggio L; Department BIOMETEC, University of Catania, Catania, Italy., Zito R; Department PROMISE, University of Palermo, Palermo, Italy., Vicario N; Department BIOMETEC, University of Catania, Catania, Italy., Saoca C; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy., Pennisi G; Department PROMISE, University of Palermo, Palermo, Italy., Cabibi D; Department PROMISE, University of Palermo, Palermo, Italy., Lazzarino G; Department BIOMETEC, University of Catania, Catania, Italy., Fracanzani AL; Medicine & Metabolic Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Dongiovanni P; Medicine & Metabolic Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy., Valenti L; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy., Petta S; Department PROMISE, University of Palermo, Palermo, Italy., Volti GL; Department BIOMETEC, University of Catania, Catania, Italy., Grimaudo S; Department PROMISE, University of Palermo, Palermo, Italy.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2024 Jan; Vol. 80 (1), pp. 10-19. Date of Electronic Publication: 2023 Oct 25.
DOI: 10.1016/j.jhep.2023.09.020
Abstrakt: Background & Aims: Sirtuin 5, encoded by the SIRT5 gene, is a NAD + -dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD).
Methods: The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography.
Results: In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels.
Conclusions: The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD.
Impact and Implications: In this study we discovered that the SIRT5 rs12216101 T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.
(Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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