Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor γ Expression

Abstract

Liver X receptors (LXRs) are nuclear hormone receptors that regulate cholesterol and fatty acid metabolism in liver tissue and in macrophages. Although LXR activation enhances lipogenesis, it is not well understood whether LXRs are involved in adipocyte differentiation. Here, we show that LXR activation stimulated the execution of adipogenesis, as determined by lipid droplet accumulation and adipocyte-specific gene expression in vivo and in vitro. In adipocytes, LXR activation with T0901317 primarily enhanced the expression of lipogenic genes such as the ADD1/SREBP1c and FAS genes and substantially increased the expression of the adipocyte-specific genes encoding PPARγ (peroxisome proliferator-activated receptor γ) and aP2. Administration of the LXR agonist T0901317 to lean mice promoted the expression of most lipogenic and adipogenic genes in fat and liver tissues. It is of interest that the PPARγ gene is a novel target gene of LXR, since the PPARγ promoter contains the conserved binding site of LXR and was transactivated by the expression of LXRα. Moreover, activated LXRα exhibited an increase of DNA binding to its target gene promoters, such as ADD1/SREBP1c and PPARγ, which appeared to be closely associated with hyperacetylation of histone H3 in the promoter regions of those genes. Furthermore, the suppression of LXRα by small interfering RNA attenuated adipocyte differentiation. Taken together, these results suggest that LXR plays a role in the execution of adipocyte differentiation by regulation of lipogenesis and adipocyte-specific gene expression.

We are grateful to Hueng-Sik Choi and Heekyung Chung for critically reading the manuscript. We also thank Bruce M. Spiegelman and Evan Rosen for MEFs of PPARγ knockout mice.

This work was supported in part by grants from the Stem Cell Research Center of the 21st Century Frontier Research Program (grant SC13150), the Molecular and Cellular BioDiscovery Research Program (grant M1-0106-02-0003), and the 21st Century Frontier Projects-The National R&D Projects for Development of Novel Biological Modulators (grant CBM1-A300-001-1-0-1), Ministry of Science and Technology, Republic of Korea. This work was also supported in part by a grant from the Ministry of Maritime Affairs and Fisheries to H. Kang, as well as by a grant from the Swedish Science Council to J.-Å. Gustafsson. J. B. Seo, W. S. Kim, J. Ham, H. Kang, and J. B. Kim are supported by a BK21 Research Fellowship from the Ministry of Education and Human Resources Development.