HDL MODULATES GLUCOSE METABOLISM IN CARDIOMYOCYTES — ASN Events
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HDL MODULATES GLUCOSE METABOLISM IN CARDIOMYOCYTES (#174)

Sarah E Heywood 1 , Darren C Henstridge 1 , Andrew L Carey 1 , Lea M Delbridge 2 , Bronwyn A Kingwell 1 , Andrew Siebel 1
  1. BakerIDI Institute, Melbourne, Vic, Australia
  2. Department of Physiology, University of Melbourne , Melbourne , Vic, Australia

The effects of HDL cholesterol within the coronary vasculature are well understood, however its direct effects on the myocardium remain to be elucidated. We have previously shown that HDL regulates glucose metabolism in an AMP-activated protein kinase (AMPK) dependent manner within skeletal muscle. Whether this same mechanism acts within cardiac muscle is unknown. We sought to determine the effect of HDL on myocardial glucose uptake, glycolysis, oxidative metabolism and the associated intracellular signalling mechanisms.

METHODS: Neonatal rat ventricular cardiomyocytes were grown in 5mmol/L glucose for 3 days. Glucose uptake was determined following 20min treatment with HDL (50μg/mL) using 2-[1,2-3H]-deoxy-D-glucose.  Cardiomyocytes were incubated with HDL (25, 50 and 100μg/mL) for 1hr prior to a glycolytic or mitochondrial stress test using the Seahorse XF-24 bioanalyser. Phospho (p)-Akt, pAS160 and pAMPK were measured via western blotting following 5 and 10min incubation with 50μg/mL HDL.

RESULTS: HDL treatment increased glucose uptake (47%±10%; P<0.05 compared to control). Treatment with 50 and 100μg/mL HDL increased glycolytic rate (43±8% and 49±9% respectively; P<0.001), maximal glycolytic capacity (48±4% and 37±5% respectively; P<0.01) and glycolytic reserve (68±13% and 76±17% respectively; P<0.001). These doses also increased basal respiration (40±8% and 38±14% respectively; P<0.001) and ATP turnover (48±8% and 58±24% respectively; P<0.05). Acute treatment with HDL increased levels of pAKT and pAS160 at 5 and 10min (pAKT:17.5±6, 11.4±3 fold change; pAS160: 3.6±1.1, 6.8±2.3 fold change respectively; P<0.05), but not pAMPK.

CONCLUSION: HDL treatment increases glucose uptake and glycolysis. Rapid activation of the Akt signalling pathway and downstream target AS160, a regulator of GLUT4 translocation, via HDL may be the mechanism controlling these changes. HDL also increases basal mitochondrial respiration and ATP turnover. Increases in both glycolytic and mitochondrial respiratory capacity may provide protection against ATP depletion during ischaemia-reperfusion and subsequent myocardial cell damage. This may be particularly relevant in the diabetic setting where ischaemic heart disease is a major cause of morbidity and mortality.

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