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Papers In Press, published online ahead of print January 1, 2004
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Howard Hughes Medical Institute, UCLA School of Medicine, Los Angeles, CA 90095-1662
Corresponding Author: ptontonoz{at}mednet.ucla.edu
Recent studies have highlighted the importance of the liver receptors a and b (LXRa and LXRb) in lipid homeostasis in liver, intestine and macrophages. The adipocyte also plays a central role in lipid metabolism, however, comparatively little is known about the function of LXRs in this cell type. Both LXRs are highly expressed in fat and the expression of LXRa increases during adipogenesis. Furthermore, previous work has shown that LXRa expression is induced by PPARg, the master regulator of fat cell differentiation. In the present study, we investigate the role of LXRs in adipocyte differentiation and adipogenic gene expression and their potential cross-talk with the PPARg pathway. We demonstrate that synthetic LXR agonists have no significant effect on the differentiation of 3T3-F442A or 3T3-L1 preadipocytes in vitro, and do not alter the expression of differentiation-linked PPARg target genes in vivo. Moreover, retroviral expression of LXRa in NIH-3T3 cells does not alter the adipogenic potential of these cells, and neither augments nor inhibits the ability of PPARg to trigger differentiation. Microarray analysis of the effects of synthetic LXR agonist in cultured adipocytes reveals that LXRs are important regulators of adipocyte gene expression. We identify the multifunction lipid carrier protein apolipoprotein D (apoD) and the lipogenic protein Spot 14 as novel LXR responsive genes both in vitro and in vivo. Finally, we show that LXR controls apoD expression through direct binding of LXR/RXR heterodimers to an LXR response element in the apoD promoter. Thus, although LXRs do not influence adipocyte differentiation or lipid accumulation per se, these receptors are likely to play an important role in the modulation of lipid metabolism in adipocytes.
Revised on December 15, 2003
Accepted on December 24, 2003
Liver X receptors are regulators of adipocyte gene expression but not differentiation. Identification of apoD as a direct target
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