Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.
Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.
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DOI：
10.1155/2013/865604
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发表时间：
2013
期刊：
影响因子：
2.9
通讯作者：
Schroeder F
中科院分区：
文献类型：
--
作者：
Huang H;McIntosh AL;Martin GG;Petrescu AD;Landrock KK;Landrock D;Kier AB;Schroeder F
虽然TOFA（乙酰辅酶A羧化酶抑制剂）和C75（脂肪酸合成酶抑制剂）通过抑制脂肪酸合成来防止脂质蓄积，但作用机制并不简单地由单独抑制酶来解释。肝脂肪酸结合蛋白（L-FABP）是长链脂肪酸信号传导至细胞核内过氧化物酶体增殖物激活受体α（PPARα）的介导因子，与TOFA及其活化的CoA硫酯TOFyl-CoA具有高亲和力，而与C75和C75-CoA具有低亲和力。TOFA和C75-CoA的结合显著改变了L-FABP的二级结构。在野生型（WT）小鼠培养的原代肝细胞中，高浓度（20 mM）但非生理性（6 mM）葡萄糖赋予TOFA和C75诱导脂肪酸β-氧化酶CPT 1A、CPT 2和ACOX 1的PPARα转录的能力。 然而，L-FABP基因切除取消了TOFA和C75在高糖背景下的作用。这些效应与未酯化脂肪酸的细胞水平增加无关，而是与细胞内葡萄糖增加有关。这些结果表明，L-FABP可能作为细胞内脂肪酸合成抑制剂结合蛋白，在血糖水平与未控制的糖尿病相似的情况下，促进TOFA和C75介导的PPARα诱导。
While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α (PPARα) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPARα transcription of the fatty acid β-oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPARα in the context of high glucose at levels similar to those in uncontrolled diabetes.
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影响因子：
7.3
作者：
Chuang, Sara;Velkov, Tony;Scanlon, Martin J.
通讯作者：
Scanlon, Martin J.
影响因子：
2.7
作者：
Fehr, M;Lalonde, S;Frommer, WB
通讯作者：
Frommer, WB
影响因子：
4.8
作者：
Berrone, E;Beltramo, E;Porta, M
通讯作者：
Porta, M
影响因子：
158.5
作者：
Cline, GW;Petersen, KF;Shulman, GI
通讯作者：
Shulman, GI
DOI：
10.1073/pnas.89.10.4653
发表时间：
1992-05-15
影响因子：
11.1
作者：
GOTTLICHER, M;WIDMARK, E;GUSTAFSSON, JA
通讯作者：
GUSTAFSSON, JA