Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways
Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways
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DOI：
10.1194/jlr.m009407
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发表时间：
2010-11-01
影响因子：
6.5
通讯作者：
Mashek, Douglas G.
中科院分区：
文献类型：
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作者：
Bu, So Young;Mashek, Douglas G.
长链酰基辅酶 A 合成酶 (ACSL) 和脂肪酸转运蛋白 (FATP) 在脂肪酸 (FA) 进行下游代谢之前将其激活为酰基辅酶 A。在众多 ACSL 和 FATP 亚型中，ACSL5 主要在三酰甘油 (TAG) 合成率高的组织中表达，表明它可能在脂质代谢中具有合成代谢作用。为了表征 ACSL5 在肝脏能量代谢中的作用，我们使用小干扰 RNA (siRNA) 敲低大鼠原代肝细胞中的 ACSL5。与转染对照 siRNA 的细胞相比，ACSL5 表达的抑制显着减少 FA 诱导的脂滴形成。代谢标记研究进一步扩展了这些发现，表明 ACSL5 敲低导致 [1-C-14] 油酸或乙酸掺入细胞内 TAG、磷脂和胆固醇酯减少，但不改变 FA 摄取或脂肪生成基因表达。 ACSL5 敲低还减少了肝脏 TAG 分泌，与观察到的中性脂质合成减少成比例。 ACSL5 敲除不会改变脂质周转或介导胰岛素对脂质代谢的影响。用 ACSL5 siRNA 处理的肝细胞增加了 FA 氧化速率，但未改变 PPAR-α 活性和靶基因表达。这些结果表明 ACSL5 激活 FA 并将其引导至合成代谢途径，因此是肝脏 FA 代谢的重要分支点。-Bu，S. Y. 和 D. G. Mashek。肝长链酰基辅酶 A 合成酶 5 介导合成代谢和分解代谢途径之间的脂肪酸通道。 J.脂质研究。 2010. 51: 3270-3280。
Long-chain acyl-CoA synthetases (ACSLs) and fatty acid transport proteins (FATPs) activate fatty acids (FAs) to acyl-CoAs prior to their downstream metabolism. Of numerous ACSL and FATP isoforms, ACSL5 is expressed predominantly in tissues with high rates of triacylglycerol (TAG) synthesis, suggesting it may have an anabolic role in lipid metabolism. To characterize the role of ACSL5 in hepatic energy metabolism, we used small interference RNA (siRNA) to knock down ACSL5 in rat primary hepatocytes. Compared with cells transfected with control siRNA, suppression of ACSL5 expression significantly decreased FA-induced lipid droplet formation. These findings were further extended with metabolic labeling studies showing that ACSL5 knockdown resulted in decreased [1-C-14] oleic acid or acetic acid incorporation into intracellular TAG, phospholipids, and cholesterol esters without altering FA uptake or lipogenic gene expression. ACSL5 knockdown also decreased hepatic TAG secretion proportionate to the observed decrease in neutral lipid synthesis. ACSL5 knockdown did not alter lipid turnover or mediate the effects of insulin on lipid metabolism. Hepatocytes treated with ACSL5 siRNA had increased rates of FA oxidation without changing PPAR-alpha activity and target gene expression. These results suggest that ACSL5 activates and channels FAs toward anabolic pathways and, therefore, is an important branch point in hepatic FA metabolism.-Bu, S. Y., and D. G. Mashek. Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways. J. Lipid Res. 2010. 51: 3270-3280.