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The SLC25A47 locus controls gluconeogenesis and energy expenditure
Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transp...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992842/ https://www.ncbi.nlm.nih.gov/pubmed/36812201 http://dx.doi.org/10.1073/pnas.2216810120 |
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author | Yook, Jin-Seon Taxin, Zachary H. Yuan, Bo Oikawa, Satoshi Auger, Christopher Mutlu, Beste Puigserver, Pere Hui, Sheng Kajimura, Shingo |
author_facet | Yook, Jin-Seon Taxin, Zachary H. Yuan, Bo Oikawa, Satoshi Auger, Christopher Mutlu, Beste Puigserver, Pere Hui, Sheng Kajimura, Shingo |
author_sort | Yook, Jin-Seon |
collection | PubMed |
description | Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. |
format | Online Article Text |
id | pubmed-9992842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-99928422023-03-09 The SLC25A47 locus controls gluconeogenesis and energy expenditure Yook, Jin-Seon Taxin, Zachary H. Yuan, Bo Oikawa, Satoshi Auger, Christopher Mutlu, Beste Puigserver, Pere Hui, Sheng Kajimura, Shingo Proc Natl Acad Sci U S A Biological Sciences Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis. National Academy of Sciences 2023-02-22 2023-02-28 /pmc/articles/PMC9992842/ /pubmed/36812201 http://dx.doi.org/10.1073/pnas.2216810120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Yook, Jin-Seon Taxin, Zachary H. Yuan, Bo Oikawa, Satoshi Auger, Christopher Mutlu, Beste Puigserver, Pere Hui, Sheng Kajimura, Shingo The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title | The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title_full | The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title_fullStr | The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title_full_unstemmed | The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title_short | The SLC25A47 locus controls gluconeogenesis and energy expenditure |
title_sort | slc25a47 locus controls gluconeogenesis and energy expenditure |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992842/ https://www.ncbi.nlm.nih.gov/pubmed/36812201 http://dx.doi.org/10.1073/pnas.2216810120 |
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