Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yook, Jin-Seon, Taxin, Zachary H., Yuan, Bo, Oikawa, Satoshi, Auger, Christopher, Mutlu, Beste, Puigserver, Pere, Hui, Sheng, Kajimura, Shingo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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
_version_ 1784902407312900096
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
work_keys_str_mv AT yookjinseon theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT taxinzacharyh theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT yuanbo theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT oikawasatoshi theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT augerchristopher theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT mutlubeste theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT puigserverpere theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT huisheng theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT kajimurashingo theslc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT yookjinseon slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT taxinzacharyh slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT yuanbo slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT oikawasatoshi slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT augerchristopher slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT mutlubeste slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT puigserverpere slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT huisheng slc25a47locuscontrolsgluconeogenesisandenergyexpenditure
AT kajimurashingo slc25a47locuscontrolsgluconeogenesisandenergyexpenditure