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1 Department of Medicine, Columbia University, New York, New York, USA
2 Department of Surgery, Columbia University, New York, New York, USA
3 Division of Pharmaceutical Sciences, University of Missouri, Kansas City, Missouri, USA
* To whom correspondence should be addressed. E-mail: ijg3{at}columbia.edu.
Hearts with overexpression of anchored lipoprotein lipase (LpL) by cardiomyocytes (hLpLGPI mice) develop a lipotoxic cardiomyopathy. To characterize cardiac fatty acid (FA) and triglyceride (TG) metabolism in these mice and to determine whether changes in lipid metabolism precede cardiac dysfunction, hearts from young mice were perfused in Langendorff mode with [14C]palmitate. In hLpLGPI hearts, FA uptake and oxidation were decreased by 59% and 82%, respectively. This suggests reliance upon an alternative energy source, such as TG. Indeed, these hearts oxidized 88% more TG. Hearts from young hLpLGPI mice also had greater uptake of intravenously injected cholesteryl ester-labeled Intralipid and VLDL. To determine whether perfusion of normal hearts would mimic the metabolic alterations found in hLpLGPI mouse hearts, wild-type hearts were perfused with [14C]palmitate and either human VLDL or Intralipid (0.4 mM TG). Both sources of TG reduced [14C]palmitate uptake (48% with VLDL and 45% with Intralipid) and FA oxidation (71% with VLDL and 65% with Intralipid). Addition of either heparin or an LpL inhibitor, P407, to Intralipid-containing perfusate restored [14C]palmitate uptake and confirmed that Intralipid inhibition requires local LpL. Our data demonstrate that reduced FA uptake and oxidation occur prior to mechanical dysfunction in hLpLGPI lipotoxicity. This physiology is reproduced with perfusion of hearts with TG-containing particles. Together, the results demonstrate that cardiac uptake of TG-derived FA reduces utilization of albumin-FA.
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