PMID- 28476858
OWN - NLM
STAT- MEDLINE
DCOM- 20180305
LR  - 20210512
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 58
IP  - 7
DP  - 2017 Jul
TI  - Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in 
      capillaries and abolishes LPL binding.
PG  - 1453-1461
LID - S0022-2275(20)33594-X [pii]
LID - 10.1194/jlr.M076943 [doi]
AB  - Mutation of conserved cysteines in proteins of the Ly6 family cause human 
      disease-chylomicronemia in the case of glycosylphosphatidylinositol-anchored HDL 
      binding protein 1 (GPIHBP1) and paroxysmal nocturnal hemoglobinuria in the case 
      of CD59. A mutation in a conserved cysteine in CD59 prevented the protein from 
      reaching the surface of blood cells. In contrast, mutation of conserved cysteines 
      in human GPIHBP1 had little effect on GPIHBP1 trafficking to the surface of 
      cultured CHO cells. The latter findings were somewhat surprising and raised 
      questions about whether CHO cell studies accurately model the fate of mutant 
      GPIHBP1 proteins in vivo. To explore this concern, we created mice harboring a 
      GPIHBP1 cysteine mutation (p.C63Y). The p.C63Y mutation abolished the ability of 
      mouse GPIHBP1 to bind LPL, resulting in severe chylomicronemia. The mutant 
      GPIHBP1 was detectable by immunohistochemistry on the surface of endothelial 
      cells, but the level of expression was  approximately 70% lower than in WT mice. The mutant 
      GPIHBP1 protein in mouse tissues was predominantly monomeric. We conclude that 
      mutation of a conserved cysteine in GPIHBP1 abolishes the ability of GPIHBP1 to 
      bind LPL, resulting in mislocalization of LPL and severe chylomicronemia. The 
      mutation reduced but did not eliminate GPIHBP1 on the surface of endothelial 
      cells in vivo.
CI  - Copyright (c) 2017 by the American Society for Biochemistry and Molecular Biology, 
      Inc.
FAU - Allan, Christopher M
AU  - Allan CM
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Jung, Cris J
AU  - Jung CJ
AD  - Children's Hospital Oakland Research Institute, Oakland, CA 94609.
FAU - Larsson, Mikael
AU  - Larsson M
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Heizer, Patrick J
AU  - Heizer PJ
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Tu, Yiping
AU  - Tu Y
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Sandoval, Norma P
AU  - Sandoval NP
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Dang, Tiffany Ly P
AU  - Dang TLP
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Jung, Rachel S
AU  - Jung RS
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095.
FAU - Beigneux, Anne P
AU  - Beigneux AP
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095. Electronic address: abeigneux@mednet.ucla.edu.
FAU - de Jong, Pieter J
AU  - de Jong PJ
AD  - Children's Hospital Oakland Research Institute, Oakland, CA 94609.
FAU - Fong, Loren G
AU  - Fong LG
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095. Electronic address: lfong@mednet.ucla.edu.
FAU - Young, Stephen G
AU  - Young SG
AD  - Departments of Medicine University of California Los Angeles, Los Angeles, CA 
      90095; Human Genetics, David Geffen School of Medicine, University of California 
      Los Angeles, Los Angeles, CA 90095. Electronic address: sgyoung@mednet.ucla.edu.
LA  - eng
GR  - R01 HL087228/HL/NHLBI NIH HHS/United States
GR  - P01 HL090553/HL/NHLBI NIH HHS/United States
GR  - R35 HL139725/HL/NHLBI NIH HHS/United States
GR  - R01 HL125335/HL/NHLBI NIH HHS/United States
GR  - T32 HL069766/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170505
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (GPIHBP1 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Lipoprotein)
RN  - 0 (Triglycerides)
RN  - EC 3.1.1.34 (LPL protein, human)
RN  - EC 3.1.1.34 (Lipoprotein Lipase)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Animals
MH  - CHO Cells
MH  - *Conserved Sequence
MH  - Cricetinae
MH  - Cricetulus
MH  - *Cysteine
MH  - Female
MH  - Humans
MH  - Lipoprotein Lipase/genetics/*metabolism
MH  - Mice
MH  - *Mutation
MH  - Protein Binding/genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptors, Lipoprotein/*chemistry/genetics/*metabolism
MH  - Triglycerides/blood
PMC - PMC5496041
OTO - NOTNLM
OT  - chylomicrons
OT  - endothelial cells
OT  - glycosylphosphatidylinositol-anchored HDL binding protein 1
OT  - lipids/chemistry
OT  - lipolysis and fatty acid metabolism
OT  - lipoprotein lipase
OT  - triglycerides
COIS- The authors have no financial interests to declare.
EDAT- 2017/05/10 06:00
MHDA- 2018/03/06 06:00
PMCR- 2018/07/01
CRDT- 2017/05/07 06:00
PHST- 2017/04/12 00:00 [received]
PHST- 2017/05/04 00:00 [revised]
PHST- 2017/05/10 06:00 [pubmed]
PHST- 2018/03/06 06:00 [medline]
PHST- 2017/05/07 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - S0022-2275(20)33594-X [pii]
AID - m076943 [pii]
AID - 10.1194/jlr.M076943 [doi]
PST - ppublish
SO  - J Lipid Res. 2017 Jul;58(7):1453-1461. doi: 10.1194/jlr.M076943. Epub 2017 May 5.