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Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation
Amit Kumar1, Priya Gupta1, Minakshi Rana1
1Pharmacology Division,Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Abstract:
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1-6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.
Insights
Pyruvate kinase M2 (PKM2) drives inflammation and cholesterol buildup in macrophages exposed to oxidized LDL (Ox-LDL), contributing to atherosclerosis. Inhibiting PKM2 reduces foam cell formation and promotes cholesterol efflux.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Disease Research
Background:
- Pyruvate kinase M2 (PKM2) is implicated in metabolic and inflammatory disorders.
- The specific role of PKM2 in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation remains unclear.
Purpose of the Study:
- To investigate the role of PKM2 in Ox-LDL-induced macrophage activation, inflammation, and foam cell formation.
- To elucidate the molecular mechanisms by which PKM2 influences lipid metabolism in macrophages.
Main Methods:
- Utilized murine bone marrow-derived macrophages and peritoneal macrophages.
- Employed techniques such as PKM2 shRNA, Shikonin (inhibitor), and DASA-58 (activator).
- Assessed gene and protein expression (LDH, GLUT1, IL-1β, ABCA1, ABCG1, CD36, FASN), cholesterol content, cholesterol efflux, and Ox-LDL uptake.
Main Results:
- Ox-LDL induced PKM2 phosphorylation and nuclear localization, promoting aerobic glycolysis and inflammation.
- PKM2 inhibition increased cholesterol efflux and decreased Ox-LDL uptake and foam cell formation.
- PKM2 regulates lipid uptake and efflux by interacting with SREBP-1 and influencing FASN expression.
Conclusions:
- PKM2 plays a critical role in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.
- Targeting PKM2 may offer a therapeutic strategy for atherosclerosis by modulating macrophage lipid metabolism and inflammation.
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