Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy
Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy
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DOI：
10.1152/ajpendo.00273.2004
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发表时间：
2005-06-01
影响因子：
5.1
通讯作者：
Goldberg, IJ
中科院分区：
文献类型：
--
作者：
Pillutla, P;Hwang, YYC;Goldberg, IJ
心肌细胞过表达锚定脂蛋白脂酶（LpL）的心脏（hLpL（GPI）小鼠）发生脂毒性心肌病。为了表征这些小鼠的心脏脂肪酸（FA）和甘油三酯（TG）代谢，并确定脂质代谢的变化是否先于心功能不全，年轻小鼠的心脏灌注Langendorff模式与[C-14]棕榈酸酯。在hLpL（GPI）的心脏，FA摄取和氧化分别减少了59%和82%。这表明依赖于替代能源，如TG。事实上，这些心脏氧化了88%以上的TG。年轻hLpL（GPI）小鼠的心脏也有更大的摄取静脉注射胆固醇酯标记的Intralidid和VLDL。为了确定正常心脏的灌注是否会模拟在hLpL（GPI）小鼠心脏中发现的代谢改变，用[C-14]棕榈酸酯和人VLDL或Intraperoid（0.4 mM TG）灌注野生型心脏。两种来源的TG均降低[C-14]棕榈酸摄取（VLDL为48%，Intraperoid为45%）和FA氧化（VLDL为71%，Intraperoid为65%）。将肝素或LpL抑制剂P407添加到含Intralidid的灌注液中恢复了[C-14]棕榈酸盐摄取，并证实Intralidid抑制需要局部LpL。我们的数据表明，减少FA摄取和氧化发生在机械功能障碍的hLpL（GPI）脂毒性。用含TG的颗粒灌注心脏可再现这种生理学。总之，结果表明，TG衍生的FA的心脏摄取减少了白蛋白-FA的利用。
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 [C-14]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 [C-14]palmitate and either human VLDL or Intralipid (0.4 mM TG). Both sources of TG reduced [C-14]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 [C-14]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.