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 Wy 14643 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. (C) 2002 Elsevier Science (USA). All rights reserved.