Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation[S]

被引：50

作者：

Kumar, Amit ^{[1
]}

Gupta, Priya ^{[1
]}

Rana, Minakshi ^{[1
]}

Chandra, Tulika ^{[2
]}

Dikshit, Madhu ^{[1
,3
]}

Barthwal, Manoj Kumar ^{[1
]}

机构：

[1] CSIR CDRI, Div Pharmacol, Lucknow, Uttar Pradesh, India

[2] King Georges Med Univ, Dept Transfus Med, Lucknow, Uttar Pradesh, India

[3] Translat Hlth Sci & Technol Inst, Faridabad 121001, Haryana, India

来源：

JOURNAL OF LIPID RESEARCH | 2020年 / 61卷 / 03期

关键词：

lipid; cholesterol metabolism; oxidized low density lipoprotein; CHOLESTEROL EFFLUX; GENE-EXPRESSION; ACTIVATION; ATHEROSCLEROSIS; INFLAMMATION; METABOLISM; PROMOTES; ISOFORM; TARGET;

D O I：

10.1194/jlr.RA119000382

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-1 alpha target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1 beta (IL-1 beta) mRNA expression, lactate, and secretory IL-1 beta 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-alpha, 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.

引用

页码：351 / 364

页数：14

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