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: Kenichi Matsushita, Fulvio Morello, Zhiping Zhang, Tomoko Masuda, Shiro Iwanaga, Knut R Steffensen, Jan-Åke Gustafsson, Richard E Pratt, Victor J Dzau
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 96 Issue 2 Pg. 230-8 (Feb 2016) ISSN: 1530-0307 [Electronic] United States
• PMID: 26595172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Liver X Receptors
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• Wnt Proteins
• beta Catenin

Topics

• Adipocytes (metabolism)
• Adipogenesis (physiology)
• Animals
• Cell Differentiation (physiology)
• Cells, Cultured
• Humans
• Liver X Receptors
• Mesenchymal Stem Cells (cytology)
• Mice
• Orphan Nuclear Receptors (genetics, metabolism)
• Wnt Proteins (metabolism)
• Wnt Signaling Pathway (physiology)
• beta Catenin (metabolism)