Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes
Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (<i>SLC19A1</i>) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, tra...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/337 |
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| author | Ainara Cano Mercedes Vazquez-Chantada Javier Conde-Vancells Aintzane Gonzalez-Lahera David Mosen-Ansorena Francisco J. Blanco Karine Clément Judith Aron-Wisnewsky Albert Tran Philippe Gual Carmelo García-Monzón Joan Caballería Azucena Castro María Luz Martínez-Chantar José M. Mato Huiping Zhu Richard H. Finnell Ana M. Aransay |
| author_facet | Ainara Cano Mercedes Vazquez-Chantada Javier Conde-Vancells Aintzane Gonzalez-Lahera David Mosen-Ansorena Francisco J. Blanco Karine Clément Judith Aron-Wisnewsky Albert Tran Philippe Gual Carmelo García-Monzón Joan Caballería Azucena Castro María Luz Martínez-Chantar José M. Mato Huiping Zhu Richard H. Finnell Ana M. Aransay |
| author_sort | Ainara Cano |
| collection | DOAJ |
| description | Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (<i>SLC19A1</i>) 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 <i>SLC19A1</i> was evaluated with the aid of an RT<sup>2</sup> profiler-array. After shRNA-silencing of <i>SLC19A1</i> 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 <i>SLC19A1</i>-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 <i>SLC19A1</i> was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional <i>SLC19A1</i> 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 <i>SLC19A1</i>-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 <i>SLC19A1</i> 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. |
| first_indexed | 2024-03-11T09:06:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:06:55Z |
| publishDate | 2023-01-01 |
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| series | Biomedicines |
| spelling | doaj.art-604e1f5cef3f4e0f877c63c8750f776b2023-11-16T19:16:45ZengMDPI AGBiomedicines2227-90592023-01-0111233710.3390/biomedicines11020337Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in HepatocytesAinara Cano0Mercedes Vazquez-Chantada1Javier Conde-Vancells2Aintzane Gonzalez-Lahera3David Mosen-Ansorena4Francisco J. Blanco5Karine Clément6Judith Aron-Wisnewsky7Albert Tran8Philippe Gual9Carmelo García-Monzón10Joan Caballería11Azucena Castro12María Luz Martínez-Chantar13José M. Mato14Huiping Zhu15Richard H. Finnell16Ana M. Aransay17Food Research, AZTI, Basque Research and Technology Alliance (BRTA), Parque Tecnologico de Bizkaia, Astondo Bidea, Building 609, 48160 Derio, SpainOWL Metabolomics, Parque Tecnologico de Bizkaia, Building 502, 48160 Derio, SpainDepartment of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USACIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainCIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainCIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainNutriomics Research Group, Nutrition Department, Pitié-Salpétrière Hospital, INSERM, Sorbonne Université, F-75013 Paris, FranceNutriomics Research Group, Nutrition Department, Pitié-Salpétrière Hospital, INSERM, Sorbonne Université, F-75013 Paris, FranceTeam 8 “Chronic Liver Diseases Associated with Obesity and Alcohol”, INSERM, U1065, Centre Hospitalier Universitaire de Nice, C3M, Université Côte d’Azur, 06000 Nice, FranceTeam 8 “Chronic Liver Diseases Associated with Obesity and Alcohol”, INSERM, U1065, Centre Hospitalier Universitaire de Nice, C3M, Université Côte d’Azur, 06000 Nice, FranceCIBERehd, ISCIII, 28029 Madrid, SpainCIBERehd, ISCIII, 28029 Madrid, SpainOWL Metabolomics, Parque Tecnologico de Bizkaia, Building 502, 48160 Derio, SpainCIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainCIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainDepartment of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USADepartment of Nutritional Sciences, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USACIC bioGUNE, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, SpainLow serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (<i>SLC19A1</i>) 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 <i>SLC19A1</i> was evaluated with the aid of an RT<sup>2</sup> profiler-array. After shRNA-silencing of <i>SLC19A1</i> 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 <i>SLC19A1</i>-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 <i>SLC19A1</i> was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional <i>SLC19A1</i> 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 <i>SLC19A1</i>-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 <i>SLC19A1</i> 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.https://www.mdpi.com/2227-9059/11/2/337NAFLDMAFLDfolate cycleliver lipid metabolismSNPsgenomics |
| spellingShingle | Ainara Cano Mercedes Vazquez-Chantada Javier Conde-Vancells Aintzane Gonzalez-Lahera David Mosen-Ansorena Francisco J. Blanco Karine Clément Judith Aron-Wisnewsky Albert Tran Philippe Gual Carmelo García-Monzón Joan Caballería Azucena Castro María Luz Martínez-Chantar José M. Mato Huiping Zhu Richard H. Finnell Ana M. Aransay Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes Biomedicines NAFLD MAFLD folate cycle liver lipid metabolism SNPs genomics |
| title | Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes |
| title_full | Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes |
| title_fullStr | Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes |
| title_full_unstemmed | Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes |
| title_short | Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes |
| title_sort | impaired function of solute carrier family 19 leads to low folate levels and lipid droplet accumulation in hepatocytes |
| topic | NAFLD MAFLD folate cycle liver lipid metabolism SNPs genomics |
| url | https://www.mdpi.com/2227-9059/11/2/337 |
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