Bile acids attenuate PKM2 pathway activation in proinflammatory microglia
Abstract Glycolysis is the metabolic pathway that converts glucose into pyruvate. Central nervous system (CNS) pathologies, such as spinal cord injury (SCI) and ischemia, are accompanied by an increase of the glycolytic pathway in the damaged areas as part of the inflammatory response. Pyruvate kina...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-05408-3 |
| _version_ | 1818300300648251392 |
|---|---|
| author | Lorenzo Romero-Ramírez Concepción García-Rama Siyu Wu Jörg Mey |
| author_facet | Lorenzo Romero-Ramírez Concepción García-Rama Siyu Wu Jörg Mey |
| author_sort | Lorenzo Romero-Ramírez |
| collection | DOAJ |
| description | Abstract Glycolysis is the metabolic pathway that converts glucose into pyruvate. Central nervous system (CNS) pathologies, such as spinal cord injury (SCI) and ischemia, are accompanied by an increase of the glycolytic pathway in the damaged areas as part of the inflammatory response. Pyruvate kinase is a key glycolytic enzyme that converts phosphoenolpyruvate and ADP to pyruvate and ATP. The protein has two isoforms, PKM1 and PKM2, originated from the same gene. As a homodimer, PKM2 loses the pyruvate kinase activity and acts as a transcription factor that regulates the expression of target genes involved in glycolysis and inflammation. After SCI, resident microglia and hematogenous macrophages are key inducers of the inflammatory response with deleterious effects. Activation of the bile acid receptor TGR5 inhibits the pro-inflammatory NFκB pathway in microglia and macrophages. In the present study we have investigated whether bile acids affect the expression of glycolytic enzymes and their regulation by PKM2. Bacterial lipopolysaccharide (LPS) induced the expression of PKM1, PKM2 and its target genes in primary cultures of microglial and Raw264.7 macrophage cells. SCI caused an increase of PKM2 immunoreactivity in macrophages after SCI. Pretreatment with tauroursodeoxycholic acid (TUDCA) or taurolithocholic acid (TLCA) reduced the expression of PKM2 and its target genes in cell cultures. Similarly, after SCI, TUDCA treatment reduced the expression of PKM2 in the lesion center. These results confirm the importance of PKM2 in the inflammatory response in CNS pathologies and indicate a new mechanism of bile acids as regulators of PKM2 pathway. |
| first_indexed | 2024-12-13T05:04:56Z |
| format | Article |
| id | doaj.art-4eb333749cc746d59a9d3ae02b3eed42 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T05:04:56Z |
| publishDate | 2022-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-4eb333749cc746d59a9d3ae02b3eed422022-12-21T23:58:42ZengNature PortfolioScientific Reports2045-23222022-01-0112111310.1038/s41598-022-05408-3Bile acids attenuate PKM2 pathway activation in proinflammatory microgliaLorenzo Romero-Ramírez0Concepción García-Rama1Siyu Wu2Jörg Mey3Laboratorio de Regeneración Nerviosa e Inmunidad Innata, Hospital Nacional de Parapléjicos, SESCAMLaboratorio de Regeneración Nerviosa e Inmunidad Innata, Hospital Nacional de Parapléjicos, SESCAMLaboratorio de Regeneración Nerviosa e Inmunidad Innata, Hospital Nacional de Parapléjicos, SESCAMLaboratorio de Regeneración Nerviosa e Inmunidad Innata, Hospital Nacional de Parapléjicos, SESCAMAbstract Glycolysis is the metabolic pathway that converts glucose into pyruvate. Central nervous system (CNS) pathologies, such as spinal cord injury (SCI) and ischemia, are accompanied by an increase of the glycolytic pathway in the damaged areas as part of the inflammatory response. Pyruvate kinase is a key glycolytic enzyme that converts phosphoenolpyruvate and ADP to pyruvate and ATP. The protein has two isoforms, PKM1 and PKM2, originated from the same gene. As a homodimer, PKM2 loses the pyruvate kinase activity and acts as a transcription factor that regulates the expression of target genes involved in glycolysis and inflammation. After SCI, resident microglia and hematogenous macrophages are key inducers of the inflammatory response with deleterious effects. Activation of the bile acid receptor TGR5 inhibits the pro-inflammatory NFκB pathway in microglia and macrophages. In the present study we have investigated whether bile acids affect the expression of glycolytic enzymes and their regulation by PKM2. Bacterial lipopolysaccharide (LPS) induced the expression of PKM1, PKM2 and its target genes in primary cultures of microglial and Raw264.7 macrophage cells. SCI caused an increase of PKM2 immunoreactivity in macrophages after SCI. Pretreatment with tauroursodeoxycholic acid (TUDCA) or taurolithocholic acid (TLCA) reduced the expression of PKM2 and its target genes in cell cultures. Similarly, after SCI, TUDCA treatment reduced the expression of PKM2 in the lesion center. These results confirm the importance of PKM2 in the inflammatory response in CNS pathologies and indicate a new mechanism of bile acids as regulators of PKM2 pathway.https://doi.org/10.1038/s41598-022-05408-3 |
| spellingShingle | Lorenzo Romero-Ramírez Concepción García-Rama Siyu Wu Jörg Mey Bile acids attenuate PKM2 pathway activation in proinflammatory microglia Scientific Reports |
| title | Bile acids attenuate PKM2 pathway activation in proinflammatory microglia |
| title_full | Bile acids attenuate PKM2 pathway activation in proinflammatory microglia |
| title_fullStr | Bile acids attenuate PKM2 pathway activation in proinflammatory microglia |
| title_full_unstemmed | Bile acids attenuate PKM2 pathway activation in proinflammatory microglia |
| title_short | Bile acids attenuate PKM2 pathway activation in proinflammatory microglia |
| title_sort | bile acids attenuate pkm2 pathway activation in proinflammatory microglia |
| url | https://doi.org/10.1038/s41598-022-05408-3 |
| work_keys_str_mv | AT lorenzoromeroramirez bileacidsattenuatepkm2pathwayactivationinproinflammatorymicroglia AT concepciongarciarama bileacidsattenuatepkm2pathwayactivationinproinflammatorymicroglia AT siyuwu bileacidsattenuatepkm2pathwayactivationinproinflammatorymicroglia AT jorgmey bileacidsattenuatepkm2pathwayactivationinproinflammatorymicroglia |