Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha.
Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha.
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DOI：
10.1161/circresaha.110.221713
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发表时间：
2010-07-23
影响因子：
20.1
通讯作者：
Lewandowski ED
中科院分区：
文献类型：
--
作者：
Banke NH;Wende AR;Leone TC;O'Donnell JM;Abel ED;Kelly DP;Lewandowski ED
长链脂肪酸（LCFA）是心脏提供能量的首选底物。然而，内源性三酰甘油（TAG）周转对LCFA氧化的贡献以及线粒体氧化对内源性脂质的总体依赖性在很大程度上尚未研究。我们试图确定TAG周转在支持LCFA氧化中的作用以及脂质激活核受体PPARα对这种平衡的影响。在正常小鼠（非转基因，NTG）和心脏特异性过表达PPARα（MHC-PPARα）的小鼠的离体心脏中定量TAG内的棕榈酰转换和棕榈酸氧化速率。在NTG中，TAG内棕榈酰单位的周转以及棕榈酰辅酶A再循环（4.5± 2.3 μ mol/min/gdw）比棕榈酸氧化（1.2 ±0.4）快3.75倍。棕榈酰单位转换的这种高速率表明在正常心脏中来自TAG的棕榈酰单位的优先氧化。与NTG心脏相比，PPARα过表达增加TAG周转3倍，尽管在相同的工作负荷下棕榈酸和氧气使用的乙酰辅酶A合成比例相似。MHC-PPARα心肌TAG内棕榈酰代谢（16.2 ± 2.9，P<0.05）比氧化代谢（1.3 ± 0.2）快12.5倍。MHC-PPARα中TAG周转率升高与TAG合成相关酶（Gpam、Dgat 1和Agpat 3）和脂解相关酶（Pnliprp 1）的mRNA增加相关。内源性TAG在支持正常心脏中的β-氧化中的作用比以前认为的更具动态性，并且脂解提供了用于氧化的大部分LCFA。由于慢性PPARα活化，TAG中棕榈酰周转加快，导致TAG中LCFA几乎必须氧化。
Long chain fatty acids (LCFA) are the preferred substrate for energy provision in hearts. However, the contribution of endogenous triacylglyceride (TAG) turnover to LCFA oxidation and the overall dependence of mitochondrial oxidation on endogenous lipid is largely unstudied. We sought to determine the role of TAG turnover in supporting LCFA oxidation and the influence of the lipid-activated nuclear receptor, PPARα, on this balance. Palmitoyl turnover within TAG and palmitate oxidation rates were quantified in isolated hearts, from normal mice (non-transgenic, NTG) and mice with cardiac-specific overexpression of PPARα (MHC-PPARα). Turnover of palmitoyl units within TAG, and thus palmitoyl-CoA recycling, in NTG (4.5± 2.3 μmoles/min/gdw) was 3.75-fold faster than palmitate oxidation (1.2 ±0.4). This high rate of palmitoyl unit turnover indicates preferential oxidation of palmitoyl units derived from TAG in normal hearts. PPARα overexpression augmented TAG turnover 3-fold over NTG hearts, despite similar fractions of acetyl-CoA synthesis from palmitate and oxygen use at the same workload. Palmitoyl turnover within TAG of MHC-PPARα hearts (16.2 ± 2.9, P<0.05) was 12.5-fold faster than oxidation (1.3 ± 0.2). Elevated TAG turnover in MHC-PPARα correlated with increased mRNA for enzymes involved in both TAG synthesis, Gpam, Dgat1, and Agpat3, and lipolysis, Pnliprp1. The role of endogenous TAG in supporting β-oxidation in the normal heart is much more dynamic than previously thought, and lipolysis provides the bulk of LCFA for oxidation. Accelerated palmitoyl turnover in TAG, due to chronic PPARα activation, results in near requisite oxidation of LCFA from TAG.