Peroxisome proliferator-activated receptor α is required for feedback regulation of highly unsaturated fatty acid synthesis
Peroxisome proliferator-activated receptor α is required for feedback regulation of highly unsaturated fatty acid synthesis
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DOI：
10.1194/jlr.m500237-jlr200
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发表时间：
2005-11-01
影响因子：
6.5
通讯作者：
Nakamura, MT
中科院分区：
文献类型：
--
作者：
Li, Y;Nara, TY;Nakamura, MT
Δ 6去饱和酶（D 6D）是高度不饱和脂肪酸（HUFA）合成的限速酶，由缺乏必需脂肪酸的饮食诱导。固醇调节元件结合蛋白-1c（SREBP-1c）部分介导这种诱导。特异性地，D 6D也由过氧化物酶体增殖物激活受体α（PPAR α）的配体诱导。在这里，我们报告了一种新的生理作用的过氧化物酶体增殖物激活受体α诱导基因的特异性HUFA合成必需脂肪酸缺乏的饮食。在野生型小鼠中，必需脂肪酸缺乏饮食对D 6D mRNA的诱导作用在PPAR α缺失小鼠中减弱。这种受损的D 6D诱导在PPARalpha-无效的小鼠是不归因于反馈抑制组织HUFA，因为PPARalpha-无效的小鼠有较低的HUFA在肝磷脂比野生型小鼠。此外，在必需脂肪酸缺乏的野生型小鼠中诱导了PPARalpha应答基因，表明产生了内源性PPARalpha配体。与HUFA合成基因相反，在必需脂肪酸缺乏的情况下，其他脂肪生成基因的诱导在PPAR α缺失小鼠中高于野生型小鼠，即使成熟的SREBP-1c蛋白在基因型之间没有差异。PPAR γ的表达显着增加，在PPAR α-null小鼠，可能有助于诱导基因从头脂肪生成。我们的研究表明，过氧化物酶体增殖物激活受体α，连同SREBP-1c，传感HUFA的状态，并赋予途径特异性诱导HUFA合成必需脂肪酸缺乏的饮食。
Delta 6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. Sterol regulatory element-binding protein-1c(SREBP-1c) in part mediates this induction. Paradoxically, D6D is also induced by ligands of peroxisome proliferator-activated receptor alpha (PPAR alpha). Here, we report a novel physiological role of PPAR alpha in the induction of genes specific for HUFA synthesis by essential fatty acid-deficient diets. D6D mRNA induction by essential fatty acid-deficient diets in wild-type mice was diminished in PPAR alpha-null mice. This impaired D6D induction in PPAR alpha-null mice was not attributable to feedback suppression by tissue HUFAs because PPAR alpha-null mice had lower HUFAs in liver phospholipids than did wild-type mice. Furthermore, PPAR alpha responsive genes were induced in wild-type mice under essential fatty acid deficiency, suggesting the generation of endogenous PPAR alpha ligand(s). Contrary to genes for HUFA synthesis, the induction of other lipogenic genes under essential fatty acid deficiency was higher in PPAR alpha-null mice than in wild-type mice even though mature SREBP-1c protein did not differ between the genotypes. The expression of PPAR gamma was markedly increased in PPAR alpha-null mice and might have contributed to the induction of genes for de novo lipogenesis. Our study suggests that PPAR alpha, together with SREBP-1c, senses HUFA status and confers pathway-specific induction of HUFA synthesis by essential fatty acid-deficient diets.