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Title: Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes
Authors: Cano, Ainara; Vazquez-Chantada, Mercedes; Conde-Vancells, Javier and Gonzalez-Lahera, Aintzane; Mosen-Ansorena, David; Blanco, Francisco J. J.; Clement, Karine; Aron-Wisnewsky, Judith; Tran, Albert; Gual, Philippe; Garcia-Monzon, Carmelo; Caballeria, Joan; Castro, Azucena; Martinez-Chantar, Maria Luz; Mato, Jose M.; Zhu, Huiping; Finnell, Richard H. H.; Aransay, Ana M. M.
Abstract: Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT2 profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/-1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes.
Issue Date: 2023
Publisher: MDPI
Type: Article
DOI: 10.3390/biomedicines11020337
E-ISSN: 2227-9059
Funder: CYTED 2005-2007 [FIT010000-2005-0013]
La Caixa Foundation 2007-2009 [425]
``Programme Hospitalier de Reserche Clinique�� Assistance Publique-Hopitaux de Paris [AOR 02076]
Commission of the European Communities (Collaborative Project ``Hepatic and adipose tissue and functions in the metabolic syndrome�� HEPADIP) [LSHM-CT-2005-018734]
European Union [Health-F2-2009-241762, 634413]
Gobierno Vasco-Departamento de Salud [2013111114]
MINECO [SAF2014-54658-R, CTQ2017-83810-R, PID2020-113225GB-I00, SEV-2016-0644]
Instituto de Salud Carlos III [PIE/00031]
EITB Maratoia [BIO15/CA/014]
Basque Foundation for Health Innovation and Research
BBVA Foundation
Instituto de Salud Carlos III, Spain [13/01299, 17/00535]
European FEDER funds
French Government (National Research Agency, ANR) [ANR-15-CE14-0016-0]
INSERM (France)
Association Francaise pour l'Etude du Foie (AFEF)
Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country
Innovation Technology Department of the Bizkaia County
Agence Nationale de la Recherche (ANR) [ANR-15-CE14-0016] Funding Source: Agence Nationale de la Recherche (ANR)
Appears in Publication types:Artículos científicos

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