title: Characterization of ASC-2 as an antiatherogenic transcriptional coactivator of liver X receptors in macrophages.
abstract: Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apolipoprotein E (apoE) transcripts as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low-density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-transgenic mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an antiatherogenic coactivator of LXRs in macrophages.
authors.affiliation: Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.forename: Keunhee
authors.initials: K
authors.lastname: Park
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Yeom
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Gukhan
authors.initials: G
authors.lastname: Kim
authors.forename: Jesang
authors.initials: J
authors.lastname: Ko
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Lee
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Jae W
authors.initials: JW
authors.lastname: Lee
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim