Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα
Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα
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DOI：
10.1194/jlr.m036103
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发表时间：
2013-07-01
影响因子：
6.5
通讯作者：
Semenkovich, Clay F.
中科院分区：
文献类型：
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作者：
Jensen-Urstad, Anne P. L.;Song, Haowei;Semenkovich, Clay F.
过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）α是一种核受体，在禁食期间协调肝脏代谢。脂肪酸合成酶（FAS）是一种在进食过程中将多余的卡路里储存为脂肪的酶，但它也通过促进内源性配体的合成来激活肝脏的PPAR α。在这里，我们表明，这种矛盾的关系的机制涉及FAS的差异调节，在至少两个不同的亚细胞池：细胞质和膜相关。在小鼠肝脏和培养的肝癌细胞中，细胞质与细胞膜FAS特异性活性的比率随着禁食而增加，表明在与PPAR α激活相关的条件下细胞质FAS活性更高。这种效应是由于FAS的营养依赖性和隔室选择性共价修饰。细胞质FAS优先磷酸化期间喂养或胰岛素治疗的Thr-1029和Thr-1033，侧翼的脂肪酶结构域催化残基。将这些位点突变为丙氨酸促进了PPAR α靶基因的表达。雷帕霉素诱导的哺乳动物/雷帕霉素复合物1（mTORC 1）机制靶点抑制（mTORC 1是诱导脂肪生成的摄食/胰岛素信号的介导物），减少FAS磷酸化，增加细胞质FAS酶活性，并增加PPAR α靶基因表达。雷帕霉素介导的诱导相同的基因被废除与FAS敲低。这些发现表明，肝脏FAS通道脂质合成通过特定的亚细胞区室，允许差异基因表达的基础上营养状况。
Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPAR alpha by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specific activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPAR alpha activation. This effect was due to a nutrient-dependent and compartment-selective covalent modification of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which flank a dehydratase domain catalytic residue. Mutating these sites to alanines promoted PPAR alpha target gene expression. Rapamycin-induced inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a mediator of the feeding/insulin signal to induce lipogenesis, reduced FAS phosphorylation, increased cytoplasmic FAS enzyme activity, and increased PPAR alpha target gene expression. Rapamycin-mediated induction of the same gene was abrogated with FAS knockdown. These findings suggest that hepatic FAS channels lipid synthesis through specific subcellular compartments that allow differential gene expression based on nutritional status.