Received for publication January 17, 2006.
Revised July 5, 2006.
Accepted for publication July 6, 2006.

LXR Regulation in LXR Deficient Mice: Implications for Therapeutic Targeting

Abstract

The nuclear receptors LXR and LXR are differentially expressed ligand-activated transcription factors that induce genes controlling cholesterol homeostasis and lipogenesis. Synthetic ligands for both receptor subtypes activate ABCA1-mediated cholesterol metabolism, increase reverse cholesterol transport and provide atheroprotection in mice. However, these ligands may also increase hepatic triglyceride (TG) synthesis via an SREBP-1c-dependent mechanism through a process reportedly regulated by LXR. We studied pan LXR/ agonists in LXR knockout mice to assess the contribution of LXR to regulation of selected target genes. In vitro dose response studies with macrophages from LXR -/- and -/- mice confirm an equivalent role for LXR and LXR in the regulation of ABCA1 and SREBP-1c gene expression. Cholesterol efflux studies verify that LXR can drive apoA1-dependent cholesterol mobilization from macrophages. The in vivo role of LXR in liver was further evaluated by treating LXR -/- mice with a pan LXR/ agonist. HDL-cholesterol increased without significant changes in plasma TG or VLDL. Analysis of hepatic gene expression consistently revealed less activation of ABCA1 and SREBP-1c genes in the liver of LXR null animals than in treated-WT controls. In addition, hepatic Cyp7a1 and several genes involved in fatty acid/ TG biosynthesis were not induced. In peripheral tissues from these LXR null mice, LXR activation increases ABCA1 and SREBP-1c gene expression in a parallel manner. However, putative elevation of SREBP-1c activity in these tissues did not cause hypertriglyceridemia. In summary, selective LXR activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXR-dominated lipogenesis.

Key words: Liver transporters, Regulation - physiological, Regulation - transcriptional, Cholesterol metabolism/lipoproteins

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