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.

High glucose‐induced intestinal epithelial barrier damage is aggravated by syndecan‐1 destruction and heparanase overexpression

“…Recently, studies have demonstrated that Sdc1 and HPSE are important endogenous regulators of energy balance and nutrient metabolism. HPSE overexpression and subsequent HS chains cleavage would not only cause diarrhoea, reduce reflex hyperphagia and food intake 26–28, but also alter lipoprotein lipase and clearance of triglyceride 29,30. These emphasize yet again the diverse functions of Sdc1 and HPSE, and suggest their pathological effects of Sdc1/HPSE imbalance on systemic and intestinal homoeostasis under HG condition.…”

Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus

“…1 Given that the molar concentration of FA in lipoprotein-triglyceride is ≈10-fold greater than albumin-bound circulating FA, 5 LPL-mediated hydrolysis of circulating triglyceride is suggested to be the dominant source of FA for cardiac utilization during diabetes mellitus. 30 Previously, we have reported a robust augmentation in coronary LPL activity after acute moderate diabetes mellitus and linked this observation to an increased expression of EC GPIHBP1, 19 the transporter that transfers LPL from the basolateral to the apical (luminal) side of EC where the enzyme is functional. 9 Figure 5.…”

“…19 To mimic in vivo hyperglycemia, rat aortic ECs were exposed to high glucose. Interestingly, high glucose increased GPIHBP1 mRNA ( Figure 1A, left) and protein ( Figure 1A, right panel) expression within 12 hours.…”

“…9 After moderate diabetes mellitus and an increase in vascular LPL, we previously reported that this effect could be explained by a hyperglycemia-induced increase in GPIHBP1 expression. 19 Although the DAG-PKC (diacylglycerol-protein kinase C) pathway has been implicated in a direct hyperglycemia-induced gene expression of other proteins, 31 we tested whether an indirect mechanism could also explain this increase in GPIHBP1 by high glucose. We focused on heparanase as tumor cells transform the phenotype of neighboring cells by feeding them heparanase that is capable of modulating their gene expression.…”

“…18 What remained unresolved is how this released LPL is transferred from the basolateral to the apical (luminal) side of EC, where the enzyme is functional. Recently, we reported that EC respond to hyperglycemia by increasing GPIHBP1 19 by mechanisms that are currently unclear. Data from this study suggest a novel mechanism in which heparanase-induced release of vascular endothelial growth factor (VEGF) and activation of Notch signaling is responsible for enhanced GPIHBP1 expression to regulate FA delivery and utilization by the cardiomyocyte.…”