FABP1：一种新型的肝内源性大麻素和大麻素结合蛋白,Biochemistry

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FABP1：一种新型的肝内源性大麻素和大麻素结合蛋白
Biochemistry ( IF 2.9 ) Pub Date : 2016-09-02 00:00:00 , DOI: 10.1021/acs.biochem.6b00446
Huan Huang , Avery L. McIntosh , Gregory G. Martin , Danilo Landrock , Sarah Chung , Kerstin K. Landrock , Lawrence J. Dangott , Shengrong Li ₁ , Ann B. Kier , Friedhelm Schroeder

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内源性大麻素（ECs）和大麻素是非常亲脂的分子，需要存在能将这些分子陪伴在细胞内靶标上的胞质结合蛋白。尽管三种不同的脂肪酸结合蛋白（FABP3，-5和-7）在大脑中起着这种功能，但对于这种疏水性EC和大麻素如何在肝脏中运输的了解相对较少。肝FABP最突出，即肝脏脂肪酸结合蛋白（FABP1或L-FABP），对花生四烯酸（ARA）和ARA-CoA具有高亲和力，这表明FABP1也可能结合ARA衍生的EC（AEA和2-AG）。确实，FABP1以高亲和力结合EC，如FABP1结合的荧光配体的置换和FABP1内在的酪氨酸荧光的猝灭所示。FABP1对大多数不含ARA的EC，FABP1抑制剂也有很高的亲和力，EC摄取/水解抑制剂和植物大麻素，而对于合成大麻素受体（CBR）激动剂和拮抗剂则较少。用野生型（WT）肝和FABP1基因消融（LKO）雄性小鼠的肝脏检查了生理影响。如液相色谱法和质谱法所示，FABP1基因消融显着增加了AEA，2-AG和2-OG的肝水平。这些增加不是由于EC合成酶（NAPEPLD和DAGL）的蛋白质水平增加或EC降解酶（FAAH）的水平下降，而是与FABP1的完全丧失，SCP2的水平下降（比FABP1普遍低8倍）相关，但也能与EC结合），并降低降解酶（NAAA和MAGL）的水平。

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FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

Endocannabinoids (ECs) and cannabinoids are very lipophilic molecules requiring the presence of cytosolic binding proteins that chaperone these molecules to intracellular targets. While three different fatty acid binding proteins (FABP3, -5, and -7) serve this function in brain, relatively little is known about how such hydrophobic ECs and cannabinoids are transported within the liver. The most prominent hepatic FABP, liver fatty acid binding protein (FABP1 or L-FABP), has high affinity for arachidonic acid (ARA) and ARA-CoA, suggesting that FABP1 may also bind ARA-derived ECs (AEA and 2-AG). Indeed, FABP1 bound ECs with high affinity as shown by displacement of FABP1-bound fluorescent ligands and by quenching of FABP1 intrinsic tyrosine fluorescence. FABP1 also had high affinity for most non-ARA-containing ECs, FABP1 inhibitors, EC uptake/hydrolysis inhibitors, and phytocannabinoids and less so for synthetic cannabinoid receptor (CBR) agonists and antagonists. The physiological impact was examined with liver from wild-type (WT) versus FABP1 gene-ablated (LKO) male mice. As shown by liquid chromatography and mass spectrometry, FABP1 gene ablation significantly increased hepatic levels of AEA, 2-AG, and 2-OG. These increases were not due to increased protein levels of EC synthetic enzymes (NAPEPLD and DAGL) or a decreased level of EC degradative enzyme (FAAH) but correlated with complete loss of FABP1, a decreased level of SCP2 (8-fold less prevalent than FABP1, but also binds ECs), and a decreased level of degradative enzymes (NAAA and MAGL). These data indicated that FABP1 not only is the most prominent endocannabinoid and cannabinoid binding protein but also impacts hepatic endocannabinoid levels.

更新日期：2016-09-02

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