Nuclear hormone receptor LXR alpha inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling

作者：Matsushita Kenichi; Morello Fulvio; Zhang Zhiping; Masuda Tomoko; Iwanaga Shiro; Steffensen Knut R; Gustafsson Jan Ake; Pratt Richard E; Dzau Victor J^*

来源：Laboratory Investigation, 2016, 96(2): 230-238.

DOI：10.1038/labinvest.2015.141

Nuclear hormone receptor liver X receptor-alpha (LXR alpha) 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 LXRa 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-LXR alpha (mMSC/LXR alpha/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-LXR alpha (mMSC/LXR alpha/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/LXR alpha/GFP group exhibited significantly increased Wnt expression accompanied by an increase of cellular beta-catenin (vs mMSC/GFP). These data demonstrate that LXRa 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.

• 出版日期2016-2
• 单位河北医科大学