Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism.
Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism.
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DOI：
10.3390/metabo10100385
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发表时间：
2020-09-28
期刊：
影响因子：
4.1
通讯作者：
Eckel RH
中科院分区：
文献类型：
--
作者：
Bruce KD;Dobrinskikh E;Wang H;Rudenko I;Gao H;Libby AE;Gorkhali S;Yu T;Zsombok A;Eckel RH
肝脏代谢的自主调节为非酒精性脂肪性肝病（NAFLD）的治疗提供了新的靶点。然而，调节脑-肝轴的神经元的分子特征仍不清楚。由于缺乏神经元脂蛋白脂酶（LPL）的小鼠神经元脂质感受和全身能量平衡的扰动，我们推断LPL可能是参与肝脏代谢调节的前自主神经元的组成部分。在这里，我们表明，尽管肥胖，神经元LPL减少的小鼠（NEXCreLPLflox（LPL KD））显示出改善的葡萄糖耐量和减少肝脏脂质积累与衰老相比，萎蔫型（WT）控制（LPLflox）。为了确定LPL缺乏对神经元生理学的影响，使用跨突触逆行示踪剂PRV-152在下丘脑的室旁核（PVN）中鉴定肝脏相关神经元。膜片钳研究显示LPL KD小鼠肝脏相关神经元的抑制性突触后电流减少。荧光寿命成像显微镜（FLIM）用于可视化LPL耗尽的神经元中的代谢变化。游离与结合的烟酰胺腺嘌呤二核苷酸（NADH）和黄素腺嘌呤二核苷酸（FAD）的定量显示，与对照组相比，LPL耗尽的神经元中葡萄糖利用率和TCA循环通量增加。缺乏或过度表达LPL的下丘脑细胞系的总体代谢组学概括了这些发现。我们的数据表明，LPL是一个新的特点，肝脏相关的前自主神经元的PVN。此外，LPL损失足以引起神经元底物利用和功能的变化，这可能先于肝脏代谢的变化。
The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.
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影响因子：
64.8
作者：
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影响因子：
21.3
作者：
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通讯作者：
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影响因子：
16.2
作者：
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通讯作者：
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