Feingold Kenneth, Kim Min Sun, Shigenaga Judy, Moser Art, Grunfeld Carl
Metabolism Section, Department of Medicine, University of California San Francisco, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Am J Physiol Endocrinol Metab. 2004 Feb;286(2):E201-7. doi: 10.1152/ajpendo.00205.2003.
Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
严重脓毒症会导致心脏中脂肪酸摄取和氧化减少以及心力衰竭。心脏中脂肪酸摄取和氧化所需的一些关键蛋白质已被证明在内毒素（LPS）给药后会下调。核激素受体，过氧化物酶体增殖物激活受体（PPAR）和甲状腺受体（TR），它们与视黄酸X受体（RXR）异源二聚化，是脂肪酸代谢的重要调节因子，在LPS给药后在肝脏中减少。在本研究中，我们证明LPS处理会使心脏中所有三种RXR亚型、PPARα和PPARδ以及TRα和TRβ的mRNA水平迅速且显著降低。此外，LPS给药还降低了共激活因子CREB结合蛋白（CBP）/p300、类固醇受体共激活因子（SRC）-1、SRC-3、TR相关蛋白（TRAP）220和PPARγ共激活因子（PGC）-1的表达，所有这些都是RXR-PPAR和RXR-TR转录活性所必需的。此外，LPS处理后，心脏中靶基因苹果酸酶、Spot 14、肌浆网Ca2 + -ATP酶或SERCA2、极低密度脂蛋白受体、脂肪酰辅酶A合成酶、脂肪酸转运蛋白/CD36、肉碱棕榈酰转移酶Iβ和脂蛋白脂肪酶的mRNA水平降低。LPS在心脏中诱导的RXRα、β和γ、PPARα和δ以及TRα和β以及共激活因子CBP/p300、SRC-1、SRC-3、TRAP220和PGC-1及其调节的基因表达的降低，可能解释了脂肪酸氧化所需关键蛋白质表达的降低，从而在心脏收缩力中起重要作用。这些改变可能导致脓毒症期间发生的心肌功能障碍。
