| First Author | Lü S | Year | 2018 |
| Journal | J Mol Med (Berl) | Volume | 96 |
| Issue | 6 | Pages | 585-600 |
| PubMed ID | 29732501 | Mgi Jnum | J:350748 |
| Mgi Id | MGI:7520777 | Doi | 10.1007/s00109-018-1645-6 |
| Citation | Lu S, et al. (2018) PKM2-dependent metabolic reprogramming in CD4(+) T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis. J Mol Med (Berl) 96(6):585-600 |
| abstractText | Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE(-/-) mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-gamma; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling. In this study, we further explored the important role of glycolysis-mediated metabolic reprogramming in Hcy-activated CD4(+) T cells. Mechanistically, Hcy-activated CD4(+) T cell increased the protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 by small interfering RNA reduced Hcy-induced CD4(+) T cell IFN-gamma secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2(fl/fl) mice and observed that Hcy-induced glycolysis and oxidative phosphorylation were both diminished in PKM2-deficient CD4(+) T cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-gamma secretion. T cell-depleted apolipoprotein E-deficient (ApoE(-/-)) mice adoptively transferred with PKM2-deficient CD4(+) T cells, compared to mice transferred with control cells, showed significantly decreased HHcy-accelerated early atherosclerotic lesion formation. In conclusion, this work indicates that the PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic regulation, is crucial for HHcy-induced CD4(+) T cell activation to accelerate early atherosclerosis in ApoE(-/-) mice. KEY MESSAGES: Metabolic reprogramming is crucial for Hcy-induced CD4(+) T cell inflammatory activation. Hcy activates the glycolytic-lipogenic pathway in CD4(+) T cells via PKM2. Targeting PKM2 attenuated HHcy-accelerated early atherosclerosis in ApoE(-/-) mice in vivo. |
