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Cardiac lipoprotein lipase regulation : metabolic basis for diabetic heart disease Chacko, Pulinilkunnil Thomas


During diabetes, impaired cardiac glucose transport and utilization switches energy production to exclusive R-oxidation of fatty acid (FA). We examined the contribution of cardiac lipoprotein lipase (LPL) towards providing FA to the diabetic heart. Four days of streptozotocin (STZ) or four hours of diazoxide (DZ) induced hyperglycemia enhanced LPL activity at the coronary lumen. This increased enzyme was likely unrelated to an increase in the number of endothelial LPL binding sites and suggests that binding sites for LPL in the control rat heart are partly occupied by the enzyme and diabetes rapidly initiates filling. Phloridzin treatment of STZ animals normalized plasma glucose with no effect on luminal LPL suggesting that the effects of diabetes on LPL are also largely independent of changes in blood glucose and likely involve other circulating mediators. The influence of circulating lipoprotein triglyceride (TG) hydrolysis and their lipolytic byproducts (lysophospholipids) in facilitating LPL translocation of LPL from the underlying cardiomyocyte cell surface to the coronary lumen was evaluated. Exposure of isolated control hearts to lysophosphatidylcholine (LPC) enhanced luminal LPL to levels observed following DZ. Treatment of DZ animals with either WR 1339 or N6 - cyclopentyladenosine (which inhibit lipolysis) decreased DZ induced augmentation of cardiac LPL. Our studies suggest that increases in LPL likely involve posttranslational processing via breakdown of circulating lipoprotein- TG and a LPC dependent mechanism. LPC maintained high luminal LPL through a protein kinase C (PKC) dependent mechanism and required formation of its metabolic byproduct lysophosphatidic acid (LPA). We examined whether LPL secretion following LPA involves actin cytoskeleton reassembly. Incubation of myocytes with LPA increased basal and heparin releasable (HR-LPL). Incubation of myocytes with cytochalasin D not only blocked LPA induced augmentation of HR-LPL but also abrogated filamentous actin (F actin) formation. Exposure of myocytes to LPA facilitated significant membrane translocation of RhoA, and its downstream effector Rho kinase I (ROCK 1), and blocking this effect with Y-27632 appreciably reduced basal and HR-LPL activity. Overall, our data suggest that impaired intracellular glucose utilization allows rapid vectorial transfer of LPL to unoccupied binding sites to supply the diabetic heart with excess FA potentially initiating and sustaining cardiac dysfunction during diabetes.

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