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5- and 6-desaturase gene expression by SREBP-1 and PPAR
Correspondence to: Hitoshi Shimano, To whom correspondence should be addressed., shimano-tky{at}umin.ac.jp (E-mail)
In the process of seeking sterol regulatory element-binding protein 1a (SREBP-1a) target genes, we identified and cloned a cDNA clone encoding mouse 5-desaturase (D5D). The hepatic expression of D5D as well as 6-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 (PPAR), caused a significant increase in expression of both desaturases.
The data suggested that D5D and D6D expression is dually regulated by SREBP-1c and PPAR, 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 5- and 6-desaturase gene expression by SREBP-1 and PPAR. J. Lipid Res. 2002. 43: 107–114.
Supplementary key words: lipogenesis, nutrition, polyunsaturated fatty acids, sterol regulatory element-binding protein
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