title: Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis.
abstract: Liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, plays a pivotal role in hepatic cholesterol and lipid metabolism, regulating the expression of genes associated with hepatic lipogenesis. The additional sex comb-like (ASXL) family was postulated to regulate chromatin function. Here, we investigate the roles of ASXL1 and ASXL2 in regulating LXRα activity. We found that ASXL1 suppressed ligand-induced LXRα transcriptional activity, whereas ASXL2 increased LXRα activity through direct interaction in the presence of the ligand. Chromatin immunoprecipitation (ChIP) assays showed ligand-dependent recruitment of ASXLs to ABCA1 promoters, like LXRα. Knockdown studies indicated that ASXL1 inhibits, while ASXL2 increases, lipid accumulation in H4IIE cells, similar to their roles in transcriptional regulation. We also found that ASXL1 expression increases under fasting conditions, and decreases in insulin-treated H4IIE cells and the livers of high-fat diet-fed mice. Overall, these results support the reciprocal role of the ASXL family in lipid homeostasis through the opposite regulation of LXRα.
authors: Department of Bioscience & Biotechnology, Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul 143-747, South Korea.
authors: Ui-Hyun
authors: UH
authors: Park
authors: Department of Bioscience & Biotechnology, Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul 143-747, South Korea.
authors: Mi-ran
authors: MR
authors: Seong
authors: Department of Molecular Biology, BK21 Graduate Program, Dankook University, Gyeonggi-do 448-701, South Korea.
authors: Eun-Joo
authors: EJ
authors: Kim
authors: Department of Molecular Biology, BK21 Graduate Program, Dankook University, Gyeonggi-do 448-701, South Korea.
authors: Wonhee
authors: W
authors: Hur
authors: Department of Molecular Biology, BK21 Graduate Program, Dankook University, Gyeonggi-do 448-701, South Korea.
authors: Sung Woo
authors: SW
authors: Kim
authors: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University, College of Medicine, Seoul 137-701, South Korea.
authors: Seung Kew
authors: SK
authors: Yoon
authors: Department of Bioscience & Biotechnology, Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul 143-747, South Korea. Electronic address: umsj@sejong.ac.kr.
authors: Soo-Jong
authors: SJ
authors: Um
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D050155:Lipogenesis / Q000502:physiology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C484296:ASXL2 protein, mouse; C510915:Asxl1 protein, mouse; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012097:Repressor Proteins
keywords: ASXL; ASXL1; ASXL2; ChIP; HFD; KD; LXRα; Lipogenesis; Liver; Liver X receptor; Luc; WB; Western blotting; additional sex comb-like; chromatin immunoprecitation; high fat diet; knockdown; liver X receptor alpha; luciferase; shRNA; small hairpin RNA