Dual regulation of mouse Δ5- and Δ6-desaturase gene expression by SREBP-1 and PPARα

Abstract

In the process of seeking sterol regulatory element-binding protein 1a (SREBP-1a) target genes, we identified and cloned a cDNA clone encoding mouse Δ5-desaturase (D5D). The hepatic expression of D5D as well as Δ6-desaturase (D6D) was highly activated in transgenic mice overexpressing nuclear SREBP-1a, -1c, and -2. Disruption of the SREBP-1 gene significantly reduced the expression of both desaturases in the livers of SREBP-1-deficient mice refed after fasting. The hepatic expression of both desaturases was downregulated by dietary PUFA, which were reported to suppress SREBP-1c gene expression. Sustained expression of hepatic nuclear SREBP-1c protein in the transgenic mice abolished the PUFA suppression of both desaturases. Although these data suggested that SREBP-1c regulates D5D and D6D expression, there was no difference in either the D5D or D6D mRNA level between fasted and refed normal mouse livers, indicating a mechanism for fasting induction of both desaturases. Administration of fibrate, a pharmacological ligand for peroxisome proliferator activating receptor α (PPARα), caused a significant increase in expression of both desaturases. The data suggested that D5D and D6D expression is dually regulated by SREBP-1c and PPARα, two reciprocal transcription factors for fatty acid metabolism, and could be involved in lipogenic gene regulation by producing PUFA. —Matsuzaka, T., H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Yoshikawa, A. H. Hasty, Y. Tamura, J-i. Osuga, H. Okazaki, Y. Iizuka, A. Takahashi, H. Sone, T. Gotoda, S. Ishibashi, and N. Yamada. Dual regulation of mouse Δ5- and Δ6-desaturase gene expression by SREBP-1 and PPARα. J. Lipid Res. 2002. 43: 107–114.

Keywords

• lipogenesis
• nutrition
• polyunsaturated fatty acids
• sterol regulatory element-binding protein