| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Pharmacology (G.H.K., S.-Y.Y., K.J.L., G.K., Y.H.K., H.K.L., H.W.K., S.-W.K.) and Internal Medicine (K.-U.L.), University of Ulsan College of Medicine, Seoul 138-736, Korea; Department of Life Science (K.P.), POSTECH, Pohang 790-784, Korea; School of Life Sciences and Biotechnology (G.H.K., J.K.), Korea University, Seoul 136-701, Korea; College of Pharmacy (D.-K.R.), Sungkyunkwan University, Suwon 440-746, Korea; Division of Life and Pharmaceutical Sciences (G.T.O), Ewha Womans University, Seoul 120-750, Korea; and Department of Molecular and Human Genetics (J.W.L.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Seung-Whan Kim, Department of Pharmacology, University of Ulsan College of Medicine, 388-1 PungNap-2dong, Songpa-gu, Seoul 138-736, Korea. E-mail: swkim7{at}amc.seoul.kr.
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.
NURSA Molecule Pages Link:
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
