Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice
Objective: The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. P...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002230 |
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| author | Brecht Attema Montserrat A. de la Rosa Rodriguez Evert M. van Schothorst Sander Grefte Guido JEJ. Hooiveld Sander Kersten |
| author_facet | Brecht Attema Montserrat A. de la Rosa Rodriguez Evert M. van Schothorst Sander Grefte Guido JEJ. Hooiveld Sander Kersten |
| author_sort | Brecht Attema |
| collection | DOAJ |
| description | Objective: The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking. Methods: We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47. Results: SLC25A47 was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47. Conclusion: Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding. |
| format | Article |
| id | doaj-art-6835976be28d400db2202d3da036c80b |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-6835976be28d400db2202d3da036c80b2025-02-01T04:11:58ZengElsevierMolecular Metabolism2212-87782025-02-0192102092Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese miceBrecht Attema0Montserrat A. de la Rosa Rodriguez1Evert M. van Schothorst2Sander Grefte3Guido JEJ. Hooiveld4Sander Kersten5Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the NetherlandsNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the NetherlandsHuman and Animal Physiology, Wageningen University, Wageningen, the NetherlandsHuman and Animal Physiology, Wageningen University, Wageningen, the NetherlandsNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the NetherlandsNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Corresponding author. Division of Nutritional Sciences, Cornell University, 127 Savage Hall, Ithaca, NY 14853, USA.Objective: The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking. Methods: We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47. Results: SLC25A47 was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47. Conclusion: Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.http://www.sciencedirect.com/science/article/pii/S2212877824002230LiverFastingPPARαSLC25A47MitochondriaFatty acids |
| spellingShingle | Brecht Attema Montserrat A. de la Rosa Rodriguez Evert M. van Schothorst Sander Grefte Guido JEJ. Hooiveld Sander Kersten Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice Molecular Metabolism Liver Fasting PPARα SLC25A47 Mitochondria Fatty acids |
| title | Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice |
| title_full | Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice |
| title_fullStr | Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice |
| title_full_unstemmed | Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice |
| title_short | Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice |
| title_sort | deficiency of the mitochondrial transporter slc25a47 minimally impacts hepatic lipid metabolism in fasted and diet induced obese mice |
| topic | Liver Fasting PPARα SLC25A47 Mitochondria Fatty acids |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002230 |
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