出版社:American Society for Biochemistry and Molecular Biology
摘要:6 desaturase (D6D), the rate-limiting enzyme for highly unsaturatedfatty acid (HUFA) synthesis, is induced by essential fatty acid-deficientdiets. Sterol regulatory element-binding protein-1c (SREBP-1c)in part mediates this induction. Paradoxically, D6D is alsoinduced by ligands of peroxisome proliferator-activated receptor (PPAR). Here, we report a novel physiological role of PPARin the induction of genes specific for HUFA synthesis by essentialfatty acid-deficient diets. D6D mRNA induction by essentialfatty acid-deficient diets in wild-type mice was diminishedin PPAR-null mice. This impaired D6D induction in PPAR-nullmice was not attributable to feedback suppression by tissueHUFAs because PPAR-null mice had lower HUFAs in liver phospholipidsthan did wild-type mice. Furthermore, PPAR-responsive geneswere induced in wild-type mice under essential fatty acid deficiency,suggesting the generation of endogenous PPAR ligand(s). Contraryto genes for HUFA synthesis, the induction of other lipogenicgenes under essential fatty acid deficiency was higher in PPAR-nullmice than in wild-type mice even though mature SREBP-1c proteindid not differ between the genotypes. The expression of PPARwas markedly increased in PPAR-null mice and might have contributedto the induction of genes for de novo lipogenesis.
Our study suggests that PPAR, together with SREBP-1c, sensesHUFA status and confers pathway-specific induction of HUFA synthesisby essential fatty acid-deficient diets.Abbreviations: ACBP, acyl-coenzyme A binding protein; AOX, acyl-coenzyme A oxidase; CYP, cytochrome P450; D5D, 5 desaturase; D6D, 6 desaturase; HUFA, highly unsaturated fatty acid; PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; SCD, stearoyl-coenzyme A desaturase; SREBP, sterol regulatory element-binding protein; TRB3, mammalian tribbles homolog
Supplementary key words6 desaturase • arachidonic acid • docosahexaenoic acid • essential fat deficiency • liver • peroxisome proliferator-activated receptor -null mouse • polyunsaturated fatty acid • sterol regulatory element-binding protein-1c