Nakamura M T, Nara T Y
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801, USA.
Prostaglandins Leukot Essent Fatty Acids. 2003 Feb;68(2):145-50. doi: 10.1016/s0952-3278(02)00264-8.
The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal beta-oxidation in DHA synthesis, and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.
通过合成的反馈调节，花生四烯酸和二十二碳六烯酸等高不饱和脂肪酸（HUFA）的组织含量维持在较窄范围内。δ-6去饱和酶（D6D）催化HUFA合成的第一步及限速步骤。最近发现的一例人类D6D缺乏症病例凸显了该途径的重要性。固醇调节元件结合蛋白-1c（SREBP-1c）是一种关键转录因子，可激活参与脂肪酸合成的基因的转录。我们最近鉴定出了SREBP-1c激活人类D6D基因所需的固醇调节元件（SRE）。此外，相同的SRE也介导HUFA对D6D基因的抑制作用。SREBP-1c作为D6D的关键调节因子的鉴定表明，SREBP-1c在肝脏中的主要生理功能可能是调节磷脂合成而非甘油三酯合成。过氧化物酶体增殖剂（PP）可诱导啮齿动物肝脏中的脂肪酸氧化酶和去饱和酶。然而，PP对去饱和酶 的诱导作用比对氧化酶的诱导作用慢。这种延迟诱导可能是对PP给药后HUFA氧化增加和过氧化物酶体增殖导致的HUFA需求增加的一种补偿反应。最近的研究表明过氧化物酶体β-氧化在DHA合成中起关键作用，并确定酰基辅酶A氧化酶和D-双功能蛋白为关键酶。
