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Molecular and Cellular Biology, May 2003, p. 3583-3592, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3583-3592.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activating Signal Cointegrator 2 Required for Liver Lipid Metabolism Mediated by Liver X Receptors in Mice

Seung-Whan Kim,1 Keunhee Park,1 Eunyee Kwak,1 Eunho Choi,1 Seunghee Lee,1 Jungyeob Ham,2 Heonjoong Kang,2 Jong Man Kim,3 Seung Yong Hwang,3 Young-Yun Kong,1 Keesook Lee,4 and Jae Woon Lee1*

Department of Life Science, Pohang University of Science and Technology, Pohang 790-784,1 School of Earth and Environmental Sciences, Seoul National University, Seoul 151-742,2 Department of Biochemistry and Molecular Biology and GenoCheck Co. Ltd., Hanyang University, Ansan 425-791,3 Hormone Research Center, Chonnam National University, Kwangju 500-757, Korea4

Received 24 October 2002/ Returned for modification 12 December 2002/ Accepted 14 February 2003

Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXR{alpha}-/- mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXR{alpha} in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.

* Corresponding author. Mailing address: Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea. Phone: 82-54-279-2129. Fax: 82-54-279-8374. E-mail: jaewoon{at}postech.ac.kr.

Molecular and Cellular Biology, May 2003, p. 3583-3592, Vol. 23, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.10.3583-3592.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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