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

Takashi Matsuzaka,Hitoshi Shimano,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,Nobuhiro Yamada

doi:10.1016/s0022-2275(20)30465-x

Takashi Matsuzaka, Hitoshi Shimano + Show 14 more

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https://doi.org/10.1016/s0022-2275(20)30465-x

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Abstract

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.

Highlights

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
We found a human homolog (GenBank ID number AK027031) of mouse fatty acyl-CoA elongase (FACE) after searching BLAST database
The COOH terminus of the FACE polypeptide contains a lysine residue in position Ϫ3 (KKXX-like motif), suggesting that the predicted protein is located in the endoplasmic reticulum (ER) membrane (Fig. 1B) [32]

Summary

Introduction

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. 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.—Matsuzaka, T., H. Several enzymes involved in the elongation of long-chain fatty acids in non-mammalian cells have been identified One such family consists of the yeast ELO genes. HELO1, as a member of HELO family cloned by homology to ELO2, is involved in the elongation of PUFAs and monounsaturated fatty acids, whereas the specific activity of HELO2 has not been not identified [9] These elongase could consist of a family that share a common structure of at least five membrane-spanning regions and a single histidine-box motif

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