PMID- 34473994
OWN - NLM
STAT- MEDLINE
DCOM- 20211125
LR  - 20211125
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 297
IP  - 4
DP  - 2021 Oct
TI  - Metabolic flexibility maintains proliferation and migration of FGFR 
      signaling-deficient lymphatic endothelial cells.
PG  - 101149
LID - S0021-9258(21)00950-9 [pii]
LID - 10.1016/j.jbc.2021.101149 [doi]
LID - 101149
AB  - Metabolic flexibility is the capacity of cells to alter fuel metabolism in 
      response to changes in metabolic demand or nutrient availability. It is critical 
      for maintaining cellular bioenergetics and is involved in the pathogenesis of 
      cardiovascular disease and metabolic disorders. However, the regulation and 
      function of metabolic flexibility in lymphatic endothelial cells (LECs) remain 
      unclear. We have previously shown that glycolysis is the predominant metabolic 
      pathway to generate ATP in LECs and that fibroblast growth factor receptor (FGFR) 
      signaling controls lymphatic vessel formation by promoting glycolysis. Here, we 
      found that chemical inhibition of FGFR activity or knockdown of FGFR1 induces 
      substantial upregulation of fatty acid beta-oxidation (FAO) while reducing 
      glycolysis and cellular ATP generation in LECs. Interestingly, such compensatory 
      elevation was not observed in glucose oxidation and glutamine oxidation. 
      Mechanistic studies show that FGFR blockade promotes the expression of carnitine 
      palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of FAO; this is achieved 
      by dampened extracellular signal-regulated protein kinase activation, which in 
      turn upregulates the expression of the peroxisome proliferator-activated receptor 
      alpha. Metabolic analysis further demonstrates that CPT1A depletion decreases 
      total cellular ATP levels in FGFR1-deficient rather than wildtype LECs. This 
      result suggests that FAO, which makes a negligible contribution to cellular 
      energy under normal conditions, can partially compensate for energy deficiency 
      caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect 
      of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our 
      study identified a key role of metabolic flexibility in modulating the effect of 
      FGFR signaling on LEC growth.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Song, Hongyuan
AU  - Song H
AD  - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, Oklahoma, USA.
FAU - Zhu, Jie
AU  - Zhu J
AD  - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, Oklahoma, USA.
FAU - Li, Ping
AU  - Li P
AD  - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, Oklahoma, USA.
FAU - Han, Fei
AU  - Han F
AD  - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, Oklahoma, USA.
FAU - Fang, Longhou
AU  - Fang L
AD  - Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, 
      Houston Methodist Research Institute, Houston, Texas, USA; Department of 
      Ophthalmology, Blanton Eye Institute, Houston Methodist Institute for Academic 
      Medicine, Houston Methodist Research Institute, Houston, Texas, USA; Department 
      of Cardiothoracic Surgeries, Weill Cornell Medical College, Cornell University, 
      New York City, New York, USA.
FAU - Yu, Pengchun
AU  - Yu P
AD  - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 
      Oklahoma City, Oklahoma, USA; Department of Cell Biology, University of Oklahoma 
      Health Sciences Center, Oklahoma City, Oklahoma, USA. Electronic address: 
      Pengchun-Yu@omrf.org.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210830
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (PPAR alpha)
RN  - 0 (PPARA protein, human)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 2.7.10.1 (FGFR1 protein, human)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
SB  - IM
MH  - Carnitine O-Palmitoyltransferase/genetics/metabolism
MH  - *Cell Proliferation
MH  - Endothelial Cells/*metabolism
MH  - Gene Knockdown Techniques
MH  - *Glycolysis
MH  - Humans
MH  - PPAR alpha/genetics/metabolism
MH  - Receptor, Fibroblast Growth Factor, Type 1/genetics/*metabolism
MH  - *Signal Transduction
PMC - PMC8498002
OTO - NOTNLM
OT  - CPT1A
OT  - ERK
OT  - cell metabolism
OT  - cell migration
OT  - cell proliferation
OT  - fatty acid oxidation
OT  - fibroblast growth factor receptor
OT  - glycolysis
OT  - lymphatic endothelial cell
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2021/09/03 06:00
MHDA- 2021/11/26 06:00
PMCR- 2021/08/30
CRDT- 2021/09/02 20:11
PHST- 2021/07/21 00:00 [received]
PHST- 2021/08/24 00:00 [revised]
PHST- 2021/08/30 00:00 [accepted]
PHST- 2021/09/03 06:00 [pubmed]
PHST- 2021/11/26 06:00 [medline]
PHST- 2021/09/02 20:11 [entrez]
PHST- 2021/08/30 00:00 [pmc-release]
AID - S0021-9258(21)00950-9 [pii]
AID - 101149 [pii]
AID - 10.1016/j.jbc.2021.101149 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Oct;297(4):101149. doi: 10.1016/j.jbc.2021.101149. Epub 2021 
      Aug 30.