PMID- 27903739
OWN - NLM
STAT- MEDLINE
DCOM- 20170808
LR  - 20220317
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 198
IP  - 1
DP  - 2017 Jan 1
TI  - Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic 
      Reprogramming.
PG  - 170-183
AB  - The overactivation of immune cells plays an important role in the pathogenesis of 
      hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Homocysteine (Hcy) 
      activates B cell proliferation and Ab secretion; however, the underlying 
      mechanisms for these effects remain largely unknown. Metabolic reprogramming is 
      critical for lymphocyte activation and effector function. In this study, we 
      showed that Hcy-activated B cells displayed an increase in both oxidative 
      phosphorylation and glycolysis, with a tendency to shift toward the latter, as 
      well as an accumulation of intermediates in the pentose phosphate pathway, to 
      provide energy and biosynthetic substrates for cell growth and function. 
      Mechanistically, Hcy increased both the protein expression and glycolytic enzyme 
      activity of the pyruvate kinase muscle isozyme 2 (PKM2) in B cells, whereas the 
      PKM2 inhibitor shikonin restored Hcy-induced metabolic changes, as well as B cell 
      proliferation and Ab secretion both in vivo and in vitro, indicating that PKM2 
      plays a critical role in metabolic reprogramming in Hcy-activated B cells. 
      Further investigation revealed that the Akt-mechanistic target of rapamycin 
      signaling pathway was involved in this process, as the mechanistic target of 
      rapamycin inhibitor rapamycin inhibited Hcy-induced changes in PKM2 enzyme 
      activity and B cell activation. Notably, shikonin treatment effectively 
      attenuated HHcy-accelerated atherosclerotic lesion formation in apolipoprotein 
      E-deficient mice. In conclusion, our results demonstrate that PKM2 is required to 
      support metabolic reprogramming for Hcy-induced B cell activation and function, 
      and it might serve as a critical regulator in HHcy-accelerated initiation of 
      atherosclerosis.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Deng, Jiacheng
AU  - Deng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and.
FAU - Lu, Silin
AU  - Lu S
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and.
FAU - Liu, Huiying
AU  - Liu H
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and.
FAU - Liu, Bo
AU  - Liu B
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and.
FAU - Jiang, Changtao
AU  - Jiang C
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and.
FAU - Xu, Qingbo
AU  - Xu Q
AD  - Cardiovascular Division, British Heart Foundation Centre for Vascular 
      Regeneration, King's College London, London SE5 9NU, United Kingdom.
FAU - Feng, Juan
AU  - Feng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and xwang@bjmu.edu.cn juanfeng@bjmu.edu.cn.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic 
      of China; and xwang@bjmu.edu.cn juanfeng@bjmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161130
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/immunology
MH  - B-Lymphocytes/immunology/*metabolism
MH  - Chromatography, Liquid
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Gene Knockdown Techniques
MH  - Homocysteine/immunology/*metabolism
MH  - Hyperhomocysteinemia/immunology/metabolism
MH  - Lymphocyte Activation/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Polymerase Chain Reaction
MH  - Pyruvate Kinase/*metabolism
MH  - Tandem Mass Spectrometry
PMC - PMC5164882
EDAT- 2016/12/03 06:00
MHDA- 2017/08/09 06:00
PMCR- 2016/11/30
CRDT- 2016/12/02 06:00
PHST- 2016/04/07 00:00 [received]
PHST- 2016/10/24 00:00 [accepted]
PHST- 2016/12/03 06:00 [pubmed]
PHST- 2017/08/09 06:00 [medline]
PHST- 2016/12/02 06:00 [entrez]
PHST- 2016/11/30 00:00 [pmc-release]
AID - jimmunol.1600613 [pii]
AID - ji_1600613 [pii]
AID - 10.4049/jimmunol.1600613 [doi]
PST - ppublish
SO  - J Immunol. 2017 Jan 1;198(1):170-183. doi: 10.4049/jimmunol.1600613. Epub 2016 
      Nov 30.