Heparin-binding defective lipoprotein lipase is unstable and causes abnormalities in lipid delivery to tissues

The Journal of Clinical Investigation
E Peer LutzIra J Goldberg

Abstract

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 p...Continue Reading

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Citations

Jul 2, 2009·The Journal of Biological Chemistry·Nathalie GriffonDaniel J Rader
Aug 30, 2008·Journal of Lipid Research·Daisaku MasudaShizuya Yamashita
Sep 21, 2010·Clinical Medicine & Research·Sujani PoonuruRam D Pathak
Jan 29, 2016·Science Translational Medicine·Gissette Reyes-SofferHenry N Ginsberg
Apr 21, 2005·The Journal of Clinical Investigation·Victor A DroverNada A Abumrad
Feb 6, 2003·The Journal of Clinical Investigation·Hiroaki YagyuIra J Goldberg
Nov 9, 2006·Journal of Lipid Research·Britta LoefflerMartin Merkel
Jul 2, 2002·Journal of Lipid Research·Howard Wong, Michael C Schotz
May 10, 2006·Journal of Lipid Research·Nathalie GriffonDaniel J Rader
Jul 20, 2018·The Journal of Biological Chemistry·Wieneke DijkSander Kersten
Feb 9, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·Markku O PentikäinenPetri T Kovanen
Jun 20, 2006·The Journal of Biological Chemistry·Dorothe SpillmannGunilla Olivecrona
Jun 16, 2021·Atherosclerosis·Ira J GoldbergNada A Abumrad
Jan 6, 2018·Biochemistry·Cassandra K HayneSaskia B Neher

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Methods Mentioned

BETA
transgenic
PCR
ELISA
electron microscopy

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