Suppression of estrogen-related receptor α and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response
Suppression of estrogen-related receptor α and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response
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DOI：
10.1194/jlr.m500217-jlr200
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发表时间：
2005-10-01
影响因子：
6.5
通讯作者：
Grunfeld, C
中科院分区：
文献类型：
--
作者：
Kim, MS;Shigenaga, JK;Grunfeld, C
脂肪酸氧化为代谢需求高的组织提供能量。在感染和炎症引起的急性期反应（APR）期间，脂肪酸氧化减少与高甘油三酯血症相关。关于 APR 减少脂肪酸氧化的机制知之甚少。因此，我们研究了APR是否影响中链酰基辅酶A脱氢酶（MCAD）、其调节剂雌激素相关受体α（ERRα）以及ERRα的关键辅激活剂——过氧化物酶体增殖物激活受体γ辅激活剂-1α（PGC-1α）的表达。在脂多糖 (LPS) 诱导的 APR 过程中，小鼠肝脏、心脏和肾脏中 PGC-1 α、ERR α 和 MCAD 的 mRNA 水平显着降低。这种下降很快，并且在 LPS 剂量非常低的情况下发生。肝脏中的 MCAD 活性也降低了。此外，肝核提取物与 MCAD 启动子区域中发现的 ERR α 反应元件的结合在 APR 期间显着减少，表明 MCAD 基因的转录减少。通过用针对ERR α的抗体进行超移，将结合活性鉴定为ERR α。在酵母聚糖和松节油诱导的炎症过程中，这些基因的 mRNA 水平也出现类似的降低，表明 PGC-1 α、ERR α 和 MCAD 途径的抑制是感染和炎症过程中的普遍反应。我们的研究提供了 APR 减少脂肪酸氧化的潜在机制。
Fatty acid oxidation provides energy in tissues with high metabolic demands. During the acute- phase response ( APR) induced by infection and inflammation, fatty acid oxidation is decreased associated with hypertriglyceridemia. Little is known about the mechanism by which the APR decreases fatty acid oxidation. Therefore, we investigated whether the APR affects the expression of medium- chain acylcoenzyme A dehydrogenase ( MCAD), its regulator the estrogenrelated receptor alpha ( ERR alpha), and a key coactivator of ERR alpha, the peroxisome proliferator- activated receptor gamma coactivator-1 alpha ( PGC- 1 alpha). mRNA levels of PGC- 1 alpha, ERR alpha, and MCAD are markedly reduced in the liver, heart, and kidney of mice during the lipopolysaccharide ( LPS)- induced APR. The decreases were rapid and occurred at very low doses of LPS. MCAD activity in liver was also reduced. Furthermore, binding of hepatic nuclear extracts to the ERR alpha response element found in the promoter region of MCAD was significantly decreased during the APR, suggesting the decreased transcription of the MCAD gene. The binding activity was identified as ERR alpha by supershift with antibody to ERR alpha. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine- induced inflammation, indicating that suppression of the PGC- 1 alpha, ERR alpha, and MCAD pathway is a general response during infection and inflammation. Our study provides a potential mechanism by which the APR decreases fatty acid oxidation.