Tissue-specific autoregulation of the LXRalpha gene facilitates induction of apoE in mouse adipose tissue.

The functions of the liver X receptors (LXRs) are not well documented in adipose tissue. We demonstrate here that expression of the LXRalpha gene is highly induced in vivo and in vitro in mouse and human adipocytes in the presence of the synthetic LXR agonist T0901317. This autoregulation is caused by an identified LXR-responsive element motif in the mouse LXRalpha promoter, which is conserved in the human LXRalpha promoter. Using different LXR-deficient mice, we demonstrate that the basal expression level of LXRalpha is increased in LXRbeta(-/-) mice, whereas the basal expression level of LXRbeta is unchanged in LXRalpha(-/-) mice. The two LXRs can compensate for each other in mediating ligand-activated regulation of LXR target genes involved in lipid homeostasis in adipose tissue. Sterol regulatory element binding protein-1 (SREBP-1), ATP binding cassette transporter A1 (ABCA1), ABCG1, as well as apolipoprotein E (apoE) are induced in vivo by T0901317 in wild-type, LXRalpha(-/-) or LXRbeta(-/-) mice but not in LXRalpha(-/-)beta(-/-) mice. Although SREBP-1 and ABCG1 are induced in liver, muscle, and adipose tissue, the apoE, glucose transporter-4 (GLUT4), and LXRalpha genes are specifically induced only in adipose tissue. We suggest that an important aspect of LXRalpha autoregulation in adipose tissue may be to increase the level of LXRalpha over a threshold level necessary to induce the expression of certain target genes.