A novel role for central ACBP/DBI as a regulator of long-chain fatty acid metabolism in astrocytes
A novel role for central ACBP/DBI as a regulator of long-chain fatty acid metabolism in astrocytes
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DOI：
10.1111/jnc.13035
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发表时间：
2015-04-01
影响因子：
4.7
通讯作者：
Alquier, Thierry
中科院分区：
文献类型：
--
作者：
Bouyakdan, Khalil;Taib, Bouchra;Alquier, Thierry
酰辅酶A结合蛋白(ACBP)是一种广泛表达的蛋白，能与细胞内的酰辅酶A酯结合。一些研究表明，ACBP作为酰辅酶A池的前体，调节外周组织中长链脂肪酸(LCFA)的代谢。在大脑中，ACBP被称为安定结合抑制物，一种分泌性多肽，充当GABA(A)受体的变构调节剂。然而，它在中枢性LCFA代谢中的作用仍不清楚。在本研究中，我们利用ACBP缺陷小鼠和对照小鼠，研究了ACBP的细胞表达、ACBP对LCFA细胞内代谢的调控、FA分布以及FA代谢相关基因的表达。ACBP主要见于星形胶质细胞，在下丘脑内侧基底区高表达。我们证明，ACBP缺乏改变了中央LCFA-CoA谱，并损害了下丘脑片和星形胶质细胞培养中不饱和(油酸、亚麻酸)但不饱和(棕榈酸、硬脂酸)LCFA代谢通量。此外，ACBP的缺乏对皮质和下丘脑星形胶质细胞中FA代谢相关基因的表达有不同程度的影响。最后，ACBP缺乏增加了下丘脑星形胶质细胞中FA的含量，并损害了它们对棕榈酸酯的反应。总而言之，这些发现首次揭示了中央ACBP作为LCFA在星形胶质细胞内代谢的调节器。
Acyl-CoA-binding protein (ACBP) is a ubiquitously expressed protein that binds intracellular acyl-CoA esters. Several studies have suggested that ACBP acts as an acyl-CoA pool former and regulates long-chain fatty acids (LCFA) metabolism in peripheral tissues. In the brain, ACBP is known as Diazepam-Binding Inhibitor, a secreted peptide acting as an allosteric modulator of the GABA(A) receptor. However, its role in central LCFA metabolism remains unknown. In the present study, we investigated ACBP cellular expression, ACBP regulation of LCFA intracellular metabolism, FA profile, and FA metabolism-related gene expression using ACBP-deficient and control mice. ACBP was mainly found in astrocytes with high expression levels in the mediobasal hypothalamus. We demonstrate that ACBP deficiency alters the central LCFA-CoA profile and impairs unsaturated (oleate, linolenate) but not saturated (palmitate, stearate) LCFA metabolic fluxes in hypothalamic slices and astrocyte cultures. In addition, lack of ACBP differently affects the expression of genes involved in FA metabolism in cortical versus hypothalamic astrocytes. Finally, ACBP deficiency increases FA content and impairs their release in response to palmitate in hypothalamic astrocytes. Collectively, these findings reveal for the first time that central ACBP acts as a regulator of LCFA intracellular metabolism in astrocytes.