Mobility of "HSPG-bound" LPL explains how LPL is able to reach GPIHBP1 on capillaries.
In mice lacking glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), the LPL secreted by adipocytes and myocytes remains bound to heparan sulfate proteoglycans (HSPGs) on all cells within tissues. That observation raises a perplexing issue: Why isn't the freshly secreted LPL in wild-type mice captured by the same HSPGs, thereby preventing LPL from reaching GPIHBP1 on capillaries? We hypothesized that LPL-HSPG interactions are transient, allowing the LPL to detach and move to GPIHBP1 on capillaries. Indeed, we found that LPL detaches from HSPGs on cultured cells and moves to: 1) soluble GPIHBP1 in the cell culture medium; 2) GPIHBP1-coated agarose beads; and 3) nearby GPIHBP1-expressing cells. Movement of HSPG-bound LPL to GPIHBP1 did not occur when GPIHBP1 contained a Ly6 domain missense mutation (W109S), but was almost normal when GPIHBP1's acidic domain was mutated. To test the mobility of HSPG-bound LPL in vivo, we injected GPIHBP1-coated agarose beads into the brown adipose tissue of GPIHBP1-deficient mice. LPL moved quickly from HSPGs on adipocytes to GPIHBP1-coated beads, thereby depleting LPL stores on the surface of adipocytes. We conclude that HSPG-bound LPL in the interstitial spaces of tissues is mobile, allowing the LPL to move to GPIHBP1 on endothelial cells.
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
Christopher M
CM
Allan
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
Mikael
M
Larsson
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
Rachel S
RS
Jung
Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen N, Denmark and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-220 Copenhagen N, Denmark.
Michael
M
Ploug
Division of Nutritional Science, Cornell University, Ithaca, NY 14853.
André
A
Bensadoun
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095.
Anne P
AP
Beigneux
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095 lfong@mednet.ucla.edu sgyoung@mednet.ucla.edu.
Loren G
LG
Fong
Departments of Medicine University of California Los Angeles, Los Angeles, CA 90095 lfong@mednet.ucla.edu sgyoung@mednet.ucla.edu.|Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.
Stephen G
SG
Young
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002196:Capillaries / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002914:Chylomicrons / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D056945:Hep G2 Cells; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D008066:Lipolysis / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018110:Receptors, Lipoprotein / Q000235:genetics*
D002914:Chylomicrons; D003470:Culture Media; C472779:GPI-HBP1 protein, mouse; D019812:Heparan Sulfate Proteoglycans; D018110:Receptors, Lipoprotein; D008071:Lipoprotein Lipase
chylomicrons; endothelial cells; glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1; heparan sulfate proteoglycan; lipids/chemistry; lipolysis and fatty acid metabolism; lipoprotein lipase; triglycerides