Peroxisomal proliferator-activated receptor α-b deficiency induces the reprogramming of nutrient metabolism in zebrafish
Peroxisomal proliferator-activated receptor α-b deficiency induces the reprogramming of nutrient metabolism in zebrafish
复制标题
过氧化物酶体增殖物激活受体α-b缺乏诱导斑马鱼营养代谢重编程
DOI：
10.1113/jp279814
复制
发表时间：
2020-08-07
影响因子：
5.5
通讯作者：
Du, Zhen-Yu
中科院分区：
文献类型：
--
作者：
Li, Ling-Yu;Lv, Hong-Bo;Du, Zhen-Yu
脂质代谢功能障碍与多种慢性代谢性疾病的发病有关。过氧化物酶体增殖物激活受体α (PPAR α)对正常代谢稳态至关重要，特别是对脂肪酸β -氧化的调节（FAO）。然而，对其在全身营养代谢中的调节作用知之甚少。为了探索PPAR α在代谢稳态中的潜在调节作用，我们建立了斑马鱼（Danio rerio）模型。这些类突变体表现出与FAO相关的关键酶的低表达，以及组织中线粒体和过氧化物酶体FAO的低表达，这与肝脏和内脏团块中的脂质积累有关。相反，葡萄糖利用率更高，因为他们表现出较低的血糖和组织糖原浓度，以及磷酸化肌苷3-激酶/AKT通路的激活。此外，pparab缺陷斑马鱼表现出AKT/哺乳动物雷帕霉素信号靶点的激活和更高的蛋白质含量，这意味着更多的蛋白质合成和/或更低的氨基酸分解。这些数据清楚地表明，parparabdeletion减少了FAO，但增加了葡萄糖利用和蛋白质沉积以维持能量稳态。本研究为PPAR α在鱼类全身性能量代谢中的综合调控作用提供了新的认识，同时也为从比较生理学角度研究哺乳动物PPAR α的功能提供了一个有价值的模型。
Dysfunction of lipid metabolism is involved in the pathogenesis of several chronic metabolic diseases. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is essential for normal metabolic homeostasis and, in particular, for the regulation of fatty acid beta-oxidation (FAO). However, little is known about its regulation roles in systemic nutrient metabolism. To explore the underlying modulation role of PPAR alpha in metabolic homeostasis, we generated apparab-knockout zebrafish (Danio rerio) model. Thepparabmutants demonstrated lower expression of key enzymes involved in FAO, as well as lower mitochondrial and peroxisomal FAO in tissues, which was associated with lipid accumulation in liver and visceral mass. Conversely, glucose utilization was higher because they demonstrated lower blood glucose and tissue glycogen concentrations, as well as activation of the phosphoinositide 3-kinase/AKT pathway. In addition,pparab-deficient zebrafish demonstrated activation of AKT/mammalian target of rapamycin signalling and higher protein content, implying greater protein synthesis and/or lower amino acid breakdown. These data clearly revealed thatpparabdeletion reduces FAO but increases glucose utilization and protein deposition to maintain energy homeostasis. The present study provides new insights into the comprehensive regulatory role of PPAR alpha in systemic energy metabolism in fish, and this pparab-deficient zebrafish also constitutes a valuable model for investigating the functions of PPAR alpha in mammals from comparative physiology aspects.