Intrauterine growth restriction elevates circulating acylcarnitines and suppresses fatty acid metabolism genes in the fetal sheep heart.
Intrauterine growth restriction elevates circulating acylcarnitines and suppresses fatty acid metabolism genes in the fetal sheep heart.
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DOI：
10.1113/jp281415
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发表时间：
2022-03
影响因子：
5.5
通讯作者：
Thornburg, Kent L.
中科院分区：
文献类型：
--
作者：
Drake, Rachel R.;Louey, Samantha;Thornburg, Kent L.
在出生时，哺乳动物的心肌从以碳水化合物为主要能量底物转变为以游离脂肪酸为主要燃料。因此，受损的开关可能会危及新生儿的正常心脏功能。羊胎盘栓塞是一种可靠的宫内生长受限(IUGR)模型。它能抑制心肌细胞的增殖和终末分化。我们假设，在IUGR中，调节心脏脂肪酸代谢的基因的表达也会受到类似的抑制，导致脂质的处理受到损害。胎羊脐-胎盘栓塞术10天后，IUGR胎儿循环中长链脂肪酰肉碱升高(C14：Ctrl 0.012±0.005 nmol/mlvs.IUGR 0.018±0.005 nmol/mlP<0.05；C18：Ctrl 0.027±0.009 nmoL/mlvs.IUGR 0.043±0.024 nmo1/mlP<；0.05，n=12对照，n=12 IUGR)。用荧光标记的BODIPY-C12饱和游离脂肪酸在活的分离的心肌细胞中的摄取研究表明，对照组和IUGR细胞的脂滴面积和数量没有差异。肌膜脂肪酸转运蛋白(CD36、FATP6)、酰化酶(ACSL1、ACSL3)、线粒体转运蛋白(CPT1)、β-氧化酶(LCAD、HADH、ACAT1)、三羧酸循环酶(IDH)、酯化酶(PAP、DGAT)和脂滴形成调节因子(BSCL2)基因在IUGR心肌组织中的表达均受到抑制(P<0.05)。然而，这些调控基因的蛋白质水平在不同组之间没有差异。应激心肌中mRNA和蛋白质水平的这种不一致表明，在胎盘功能不全的情况下，关键的心肌酶具有适应性保护作用。我们调查了发育受限的胎儿与正常发育的胎儿相比，调节脂肪酸代谢的心脏基因的改变程度。如红色箭头所示，与对照组相比，所研究基因的信使RNA水平受到抑制。然而，双头箭头显示蛋白质水平没有受到影响。胎儿循环中的长链脂肪酰肉碱升高，提示游离脂肪酸代谢不完全。这些实验条件是否预示着心脏向脂肪酸代谢过渡的出生后阶段会出现不良后果，还需要进一步研究。
At birth, the mammalian myocardium switches from using carbohydrates as the primary energy substrate to free fatty acids as the primary fuel. Thus, a compromised switch could jeopardize normal heart function in the neonate. Placental embolization in sheep is a reliable model of intrauterine growth restriction (IUGR). It leads to suppression of both proliferation and terminal differentiation of cardiomyocytes. We hypothesized that the expression of genes regulating cardiac fatty acid metabolism would be similarly suppressed in IUGR, leading to compromised processing of lipids. Following 10 days of umbilicoplacental embolization in fetal sheep, IUGR fetuses had elevated circulating long-chain fatty acylcarnitines compared with controls (C14: CTRL 0.012 ± 0.005 nmol/ml vs. IUGR 0.018 ± 0.005 nmol/ml, P < 0.05; C18: CTRL 0.027 ± 0.009 nmol/mol vs. IUGR 0.043 ± 0.024 nmol/mol, P < 0.05, n = 12 control, n = 12 IUGR) indicative of impaired fatty acid metabolism. Uptake studies using fluorescently tagged BODIPY-C12-saturated free fatty acid in live, isolated cardiomyocytes showed lipid droplet area and number were not different between control and IUGR cells. mRNA levels of sarcolemmal fatty acid transporters (CD36, FATP6), acylation enzymes (ACSL1, ACSL3), mitochondrial transporter (CPT1), β-oxidation enzymes (LCAD, HADH, ACAT1), tricarboxylic acid cycle enzyme (IDH), esterification enzymes (PAP, DGAT) and regulator of the lipid droplet formation (BSCL2) gene were all suppressed in IUGR myocardium (P < 0.05). However, protein levels for these regulatory genes were not different between groups. This discordance between mRNA and protein levels in the stressed myocardium suggests an adaptive protection of key myocardial enzymes under conditions of placental insufficiency. We investigated the degree to which the cardiac genes that regulate fatty acid metabolism were altered in growth-restricted fetuses compared with those that grew normally. As shown by the red arrows, messenger RNA levels for the genes studied were suppressed compared with controls. However, the double-headed arrows show that protein levels were unaffected. Circulating long-chain fatty acylcarnitines in the fetus were elevated, suggesting incomplete metabolism of free fatty acids. Whether these experimental conditions portend adverse outcomes in the postnatal period as the heart transitions to fatty acid metabolism requires further study.