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Journal of Lipid Research, Vol. 43, 911-920, June 2002
Copyright © 2002 by Lipid Research, Inc.

Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs

Takashi Matsuzaka^*, Hitoshi Shimano^1,*, Naoya Yahagi, Tomohiro Yoshikawa, Michiyo Amemiya-Kudo, Alyssa H. Hasty, Hiroaki Okazaki, Yoshiaki Tamura, Yoko Iizuka, Ken Ohashi, Jun-ichi Osuga, Akimitsu Takahashi^*, Shigeru Yato^*, Hirohito Sone^*, Shun Ishibashi and Nobuhiro Yamada^*

^* Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
Department of Metabolic Diseases, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

¹ To whom correspondence should be addressed. e-mail: shimano-tky{at}umin.ac.jp

The mammalian enzyme involved in the final elongation of de novo fatty acid biosynthesis following the building of fatty acids to 16 carbons by fatty acid synthase has yet to be identified. In the process of searching for genes activated by sterol regulatory element-binding protein 1 (SREBP-1) by using DNA microarray, we identified and characterized a murine cDNA clone that is highly similar to a fatty acyl-CoA elongase gene family such as Cig30, Sscs, and yeast ELOs. Studies on the cells overexpressing the full-length cDNA indicate that the encoded protein, designated fatty acyl-CoA elongase (FACE), has a FACE activity specific for long-chains; C12-C16 saturated- and monosaturated-fatty acids. Hepatic expression of this identified gene was consistently activated in the livers of transgenic mice overexpressing nuclear SREBP-1a, -1c, or -2. FACE mRNA levels are markedly induced in a refed state after fasting in the liver and adipose tissue. This refeeding response is significantly reduced in SREBP-1 deficient mice. Dietary PUFAs caused a profound suppression of this gene expression, which could be restored by SREBP-1c overexpression. Hepatic FACE expression was also highly up-regulated in leptin-deficient ob/ob mice. Hepatic FACE mRNA was markedly increased by administration of a pharmacological agonist of liver X-activated receptor (LXR), a dominant activator for SREBP-1c expression.

These data indicated that this elongase is a new member of mammalian lipogenic enzymes regulated by SREBP-1, playing an important role in de novo synthesis of long-chain saturated and monosaturated fatty acids in conjunction with fatty acid synthase and stearoyl-CoA desaturase.

Abbreviations: ACC, acetyl-CoA carboxylase; ACBP, acyl-CoA binding protein; ACS, acyl-CoA synthetase; FACE, fatty acyl-CoA elongase; FAS, fatty acid synthase; LXR, liver X-activated receptor; RXR, retinoic acid receptor; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein; WAT, white adipose tissue

Supplementary key words sterol regulatory element-binding protein • lipogenesis • nutrition

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