Key result
Perfusion of wild-type mouse hearts with triglyceride-rich particles reduced fatty acid uptake by up to 48% and oxidation by up to 71%, reproducing abnormalities of lipotoxic cardiomyopathy.
Cardiac uptake of triglyceride-derived fatty acids reduces utilization of albumin-bound fatty acids, reproducing metabolic abnormalities that precede mechanical dysfunction in lipotoxic cardiomyopathy.
Does not yet inform clinical lipid management in cardiomyopathy; leaves open whether triglyceride-rich particles drive human lipotoxicity.
Hearts with overexpression of anchored lipoprotein lipase (LpL) by cardiomyocytes (hLpL(GPI) 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 hLpL(GPI) hearts, FA uptake and oxidation were decreased by 59 and 82%, respectively. This suggests reliance on an alternative energy source, such as TG. Indeed, these hearts oxidized 88% more TG. Hearts from young hLpL(GPI) 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 hLpL(GPI) 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 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 before mechanical dysfunction in hLpL(GPI) 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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Pillutla et al. (2005) studied Lipotoxic cardiomyopathy. Perfusion with triglyceride-rich particles (VLDL or Intralipid) vs. Normal hearts without TG perfusion was evaluated on Fatty acid uptake and oxidation. Perfusion of wild-type mouse hearts with triglyceride-rich particles reduced fatty acid uptake by up to 48% and oxidation by up to 71%, reproducing abnormalities of lipotoxic cardiomyopathy.
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