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PKM2-dependent metabolic reprogramming in CD4+ T cells is crucial for hyperhomocysteinemia-accelerated atherosclerosis

Research output: Contribution to journalArticle

Silin Lü, Jiacheng Deng, Huiying Liu, Bo Liu, Juan Yang, Yutong Miao, Jing Li, Nan Wang, Changtao Jiang, Qingbo Xu, Xian Wang, Juan Feng

Original languageEnglish
Pages (from-to)585-600
Number of pages16
JournalJournal of Molecular Medicine
Issue number6
Early online date7 May 2018
Accepted/In press29 Apr 2018
E-pub ahead of print7 May 2018
PublishedJun 2018

King's Authors


Abstract: 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)-γ; 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-γ secretion. Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre transgenic mice with PKM2fl/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-γ 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.

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