title: Nuclear hormone receptor LXRα inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling.
abstract: Nuclear hormone receptor liver X receptor-alpha (LXRα) has a vital role in cholesterol homeostasis and is reported to have a role in adipose function and obesity although this is controversial. Conversely, mesenchymal stem cells (MSCs) are suggested to be a major source of adipocyte generation. Accordingly, we examined the role of LXRα in adipogenesis of MSCs. Adult murine MSCs (mMSCs) were isolated from wild-type (WT) and LXR-null mice. Using WT mMSCs, we further generated cell lines stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) or GFP alone (mMSC/GFP) by retroviral infection. Confluent mMSCs were differentiated into adipocytes by the established protocol. Compared with MSCs isolated from WT mice, MSCs from LXR-null mice showed significantly increased adipogenesis, as determined by lipid droplet accumulation and adipogenesis-related gene expression. Moreover, mMSCs stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) exhibited significantly decreased adipogenesis compared with mMSCs overexpressing GFP alone (mMSC/GFP). Since Wnt/beta-catenin signaling is reported to inhibit adipogenesis, we further examined it. The LXR-null group showed significantly decreased Wnt expression accompanied by a decrease of cellular beta-catenin (vs WT). The mMSC/LXRα/GFP group exhibited significantly increased Wnt expression accompanied by an increase of cellular beta-catenin (vs mMSC/GFP). These data demonstrate that LXRα has an inhibitory effect on adipogenic differentiation in mMSCs with Wnt/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity-related consequences such as metabolic syndrome and may identify potential therapeutic targets.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Morello
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Cardiology, Saitama Medical University and Saitama International Medical Center, Saitama, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwanaga
authors.affiliation: Department of Bioscience and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.affiliation: Department of Bioscience and Nutrition, Karolinska Institutet, Huddinge, Sweden.|Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Institute of Medicine, Washington, DC, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D000071518:Liver X Receptors; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D051153:Wnt Proteins; D051176:beta Catenin