title: Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target.
abstract: The liver X receptors alpha and beta (LXRalpha and LXRbeta) have been shown to play important roles in lipid homeostasis in liver and macrophages, however, their function in adipose tissue is not well defined. Both LXRs are highly expressed in fat, and the expression of LXRalpha increases during adipogenesis. Furthermore, LXRalpha expression is induced by peroxisome proliferator-activated receptor gamma (PPARgamma), the master regulator of fat cell differentiation. Here we investigate the role of LXRs in adipocyte differentiation and gene expression and their potential crosstalk with the PPARgamma pathway. We demonstrate that 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 PPARgamma target genes in vivo. Moreover, retroviral expression of LXRalpha in NIH-3T3 cells does not alter the adipogenic potential of these cells and neither augments nor inhibits the action of PPARgamma. However, transcriptional profiling studies reveal that LXRs are important regulators of adipocyte gene expression. We identify the multifunction lipid carrier protein apolipoprotein D and the lipogenic protein Spot 14 as LXR responsive genes both in vitro and in vivo. Thus, although LXRs do not influence adipocyte differentiation per se, these receptors are likely to play an important role in the modulation of lipid metabolism in adipocytes.
authors.affiliation: Molecular Biology Institute, Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hummasti
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Laffitte
authors.forename: Michael A
authors.initials: MA
authors.lastname: Watson
authors.forename: Cristin
authors.initials: C
authors.lastname: Galardi
authors.forename: Lily C
authors.initials: LC
authors.lastname: Chao
authors.forename: Lakshman
authors.initials: L
authors.lastname: Ramamurthy
authors.forename: John T
authors.initials: JT
authors.lastname: Moore
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis / Q000235:genetics*; D053399:Apolipoproteins D; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors
chemical_list: C024328:APOD protein, human; D001053:Apolipoproteins; D053399:Apolipoproteins D; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C051065:THRSP protein, human; C501477:Thrsp protein, mouse; D014157:Transcription Factors