Song He Wei, Nara Takayuki Y, Nakamura Manabu T
Department of Food Science and Human Nutrition, Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Biochem Biophys Res Commun. 2002 Dec 20;299(5):832-8. doi: 10.1016/s0006-291x(02)02743-2.
Delta-6 desaturase (D6D) is the key enzyme for the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic acid (AA) and docosahexaenoic acid (DHA) in mammals. Transcription of D6D gene is activated by both sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferators (PP). This response of D6D is paradoxical because SREBP-1c transactivates genes for fatty acid synthesis in liver, while PP induce enzymes for fatty acid oxidation. We hypothesized that the induction of D6D gene by PP is a compensatory response to the increased HUFA demand caused by peroxisome proliferation and induction of fatty acid oxidation. We investigated the time-course effects of a PP, Wy14643, on the induction of HUFA metabolizing genes and HUFA profile in rat liver. The mRNA of fatty acid oxidation enzymes in the Wy14643 fed group became significantly higher than controls at 4 h and reached maximum within 28 h. In contrast, the mRNA of delta-6 and delta-5 desaturases in the Wy14643 group was not significantly higher than control at 4 h and took >28 h to reach the maximum. Despite the induction of HUFA synthetic pathway, the concentration of end products (AA and DHA) remained unchanged throughout the 4-day period in liver phospholipids and non-esterified fatty acids. Taken together, this study supports our hypothesis and suggests that peroxisome proliferation and induction of fatty acid oxidation enzymes are the major mechanisms of the induction of HUFA synthesis by PP.
δ-6去饱和酶（D6D）是哺乳动物中合成花生四烯酸（AA）和二十二碳六烯酸（DHA）等高不饱和脂肪酸（HUFA）的关键酶。D6D基因的转录由固醇调节元件结合蛋白-1c（SREBP-1c）和过氧化物酶体增殖物（PP）共同激活。D6D的这种反应看似矛盾，因为SREBP-1c可反式激活肝脏中脂肪酸合成相关基因，而PP则诱导脂肪酸氧化相关酶。我们推测，PP对D6D基因的诱导是对过氧化物酶体增殖和脂肪酸氧化诱导所导致的HUFA需求增加的一种补偿性反应。我们研究了一种PP（Wy14643）对大鼠肝脏中HUFA代谢相关基因诱导及HUFA谱的时间进程影响。Wy14643喂养组中脂肪酸氧化酶的mRNA在4小时时显著高于对照组，并在28小时内达到最大值。相比之下，Wy14643组中δ-6和δ-5去饱和酶的mRNA在4小时时并不显著高于对照组，且需要超过28小时才能达到最大值。尽管HUFA合成途径被诱导，但在整个4天期间，肝脏磷脂和非酯化脂肪酸中的终产物（AA和DHA）浓度保持不变。综上所述，本研究支持了我们的假设，并表明过氧化物酶体增殖和脂肪酸氧化酶的诱导是PP诱导HUFA合成的主要机制。
