title: Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1.
abstract: In diabetes, when glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) almost exclusively for ATP. The vascular content of lipoprotein lipase (LPL), the rate-limiting enzyme that determines circulating triglyceride clearance, is largely responsible for this FA delivery and increases following diabetes. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein [GPIHBP1; a protein expressed abundantly in the heart in endothelial cells (EC)] collects LPL from the interstitial space and transfers it across ECs onto the luminal binding sites of these cells, where the enzyme is functional. We tested whether ECs respond to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. The increased LPL and GPIHBP1 were located at the capillary lumen. In vitro, passaging EC caused a loss of GPIHBP1, which could be induced on exposure to increasing concentrations of glucose. The high-glucose-induced GPIHBP1 increased LPL shuttling across EC monolayers. GPIHBP1 expression was linked to the EC content of heparanase. Moreover, active heparanase increased GPIHBP1 gene and protein expression. Both ECs and myocyte heparan sulfate proteoglycan-bound platelet-derived growth factor (PDGF) released by heparanase caused augmentation of GPIHBP1. Overall, our data suggest that this protein "ensemble" (heparanase-PDGF-GPIHBP1) cooperates in the diabetic heart to regulate FA delivery and utilization by the cardiomyocytes. Interrupting this axis may be a novel therapeutic strategy to restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction that is characteristic of diabetes.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Amy
authors.initials: A
authors.lastname: Pei-Ling Chiu
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Fulong
authors.initials: F
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lal
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Bahira
authors.initials: B
authors.lastname: Hussein
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; and rodrigue@mail.ubc.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D015153:Blotting, Western; D002417:Cattle; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D008066:Lipolysis / Q000502:physiology; D008071:Lipoprotein Lipase / Q000096:biosynthesis*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018110:Receptors, Lipoprotein / Q000096:biosynthesis*; D000099175:Heparanase
chemical_list: D016207:Cytokines; D005947:Glucose; D005966:Glucuronidase; D008071:Lipoprotein Lipase; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; D000099175:Heparanase; C579044:GPIHBP1 protein, rat
keywords: glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1; heparanase; lipoprotein lipase; platelet-derived growth factor