Bile acids attenuate PKM2 pathway activation in proinflammatory microglia
Open accessAbstract
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.
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The anti-inflammatory activity of TUDCA has been demonstrated in LPS-stimulated primary microglial cells and BV-2 microglial cells.
“The anti-inflammatory activity of TUDCA has been demonstrated in LPS-stimulated primary microglial cells and BV-2 microglial cells.367–369”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [368]
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References 33 · Cited by 41
- Authors
- Romero-Ramírez, L., García-Rama, C., Wu, S., & Mey, J.
- Affiliations
- Maastricht University (NL)
- Venue
- Scientific Reports
- Published
- 2022-01-27
- Volume
- 12
- Issue
- 1
- Pages
- 1459-1459
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC8795255
- OpenAlex
- W4210750980
- Cited by
- 41
- References
- 33
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 12 · 2023: 6 · 2022: 6
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-02-23)
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Ministerio de Economía y Competitividad (SAF2017-89366R)
- Chinese Scholarship Council (201606300031)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- bile acids, PKM2, pyruvate kinase, glycolysis, microglia, macrophages, spinal cord injury, neuroinflammation, TGR5, tauroursodeoxycholic acid, taurolithocholic acid, lipopolysaccharide, NF-κB, PKM1
- MeSH terms
- RAW 264.7 Cells, Neuroinflammatory Diseases, Animals, Bile Acids and Salts, Disease Models, Animal, Glycolysis, Humans, Isoenzymes, Lipopolysaccharides, Macrophages, Male, Pyruvate Kinase, Spinal Cord Injuries, Microglia, Receptors, G-Protein-Coupled, Mice, Rats, Primary Cell Culture
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