PMID- 11342582
OWN - NLM
STAT- MEDLINE
DCOM- 20010607
LR  - 20181113
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 107
IP  - 9
DP  - 2001 May
TI  - Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities 
      in lipid delivery to tissues.
PG  - 1183-92
AB  - Lipoprotein lipase (LpL) binding to heparan sulfate proteoglycans (HSPGs) is 
      hypothesized to stabilize the enzyme, localize LpL in specific capillary beds, 
      and route lipoprotein lipids to the underlying tissues. To test these hypotheses 
      in vivo, we created mice expressing a human LpL minigene (hLpL(HBM)) carrying a 
      mutated heparin-binding site. Three basic amino acids in the carboxyl terminal 
      region of LpL were mutated, yielding an active enzyme with reduced heparin 
      binding. Mice expressing hLpL(HBM) accumulated inactive human LpL (hLpL) protein 
      in preheparin blood. hLpL(HBM) rapidly lost activity during a 37 degrees C 
      incubation, confirming a requirement for heparin binding to stabilize LPL: 
      Nevertheless, expression of hLpL(HBM) prevented the neonatal demise of LpL 
      knockout mice. On the LpL-deficient background hLpL(HBM) expression led to 
      defective targeting of lipids to tissues. Compared with mice expressing native 
      hLpL in the muscle, hLpL(HBM) transgenic mice had increased postprandial FFAs, 
      decreased lipid uptake in muscle tissue, and increased lipid uptake in kidneys. 
      Thus, heparin association is required for LpL stability and normal physiologic 
      functions. These experiments confirm in vivo that association with HSPGs can 
      provide a means to maintain proteins in their stable conformations and to anchor 
      them at sites where their activity is required.
FAU - Lutz, E P
AU  - Lutz EP
AD  - Department of Medicine, Columbia University, New York, New York 10032, USA.
FAU - Merkel, M
AU  - Merkel M
FAU - Kako, Y
AU  - Kako Y
FAU - Melford, K
AU  - Melford K
FAU - Radner, H
AU  - Radner H
FAU - Breslow, J L
AU  - Breslow JL
FAU - Bensadoun, A
AU  - Bensadoun A
FAU - Goldberg, I J
AU  - Goldberg IJ
LA  - eng
GR  - R01 HL045095/HL/NHLBI NIH HHS/United States
GR  - HL56984/HL/NHLBI NIH HHS/United States
GR  - R37 HL045095/HL/NHLBI NIH HHS/United States
GR  - HL45095/HL/NHLBI NIH HHS/United States
GR  - HL 14990/HL/NHLBI NIH HHS/United States
GR  - HL62301/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Amino Acids, Diamino)
RN  - 0 (Chylomicrons)
RN  - 0 (Fat Emulsions, Intravenous)
RN  - 0 (Heparan Sulfate Proteoglycans)
RN  - 0 (Palmitates)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.1.1.34 (Lipoprotein Lipase)
SB  - IM
MH  - Amino Acids, Diamino/genetics
MH  - Animals
MH  - Binding Sites/genetics
MH  - Blotting, Northern
MH  - Chromatography, Affinity
MH  - Chylomicrons/metabolism
MH  - Enzyme Stability
MH  - Fat Emulsions, Intravenous/metabolism
MH  - Female
MH  - Heparan Sulfate Proteoglycans/*metabolism
MH  - Heparin/*metabolism
MH  - Humans
MH  - Lipoprotein Lipase/blood/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Muscles/metabolism/pathology
MH  - Mutation
MH  - Palmitates/metabolism
PMC - PMC209279
EDAT- 2001/05/09 10:00
MHDA- 2001/06/08 10:01
PMCR- 2001/05/01
CRDT- 2001/05/09 10:00
PHST- 2001/05/09 10:00 [pubmed]
PHST- 2001/06/08 10:01 [medline]
PHST- 2001/05/09 10:00 [entrez]
PHST- 2001/05/01 00:00 [pmc-release]
AID - 11774 [pii]
AID - 10.1172/JCI11774 [doi]
PST - ppublish
SO  - J Clin Invest. 2001 May;107(9):1183-92. doi: 10.1172/JCI11774.