Activating signal cointegrator 2 required for liver lipid metabolism mediated by liver X receptors in mice

Seung Whan Kim, Keunhee Park, Eunyee Kwak, Eunho Choi, Seunghee Lee, Jungyeob Ham, Heonjoong Kang, Jong Man Kim, Seung Yong Hwang, Young Yun Kong, Keesook Lee, Jae Woon Lee

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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 LXRα-/- mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRα 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.

Original languageEnglish (US)
Pages (from-to)3583-3592
Number of pages10
JournalMolecular and cellular biology
Volume23
Issue number10
DOIs
StatePublished - May 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kim, S. W., Park, K., Kwak, E., Choi, E., Lee, S., Ham, J., Kang, H., Kim, J. M., Hwang, S. Y., Kong, Y. Y., Lee, K., & Lee, J. W. (2003). Activating signal cointegrator 2 required for liver lipid metabolism mediated by liver X receptors in mice. Molecular and cellular biology, 23(10), 3583-3592. https://doi.org/10.1128/MCB.23.10.3583-3592.2003