Liver X Receptor (LXR)-β Regulation in LXRα-Deficient Mice: Implications for Therapeutic Targeting

Abstract

The nuclear receptors liver X receptor (LXR) 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 ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol metabolism, increase reverse cholesterol transport, and provide atheroprotection in mice. However, these ligands may also increase hepatic triglyceride (TG) synthesis via a sterol response element binding protein 1c (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 the regulation of selected target genes. In vitro dose-response studies with macrophages from LXR␣Ϫ/Ϫ and ␤Ϫ/Ϫ 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␣Ϫ/Ϫ mice with a pan-LXR␣/␤ agonist. Highdensity lipoprotein (HDL) cholesterol increased without significant changes in plasma TG or very low density lipoprotein. 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 wild-type 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.There is great interest in targeting LXR nuclear receptors and their modulation for the treatment of atherosclerosis. These transcription factors play a critical role in the control of cholesterol homeostasis and have been the topic of several recent reviews (Jaye,

Liver X receptors as regulators of metabolism

“…In mice lacking LXRα, but not in those lacking LXRβ, removal of cholesterol from the body is severely impaired (18,36). Conversely, systemic activation of LXR with LXR agonists reduces whole-body cholesterol levels in LXR WT mice and raises HDL levels in the plasma (40)(41)(42) confirming that in mice, LXR is the key regulator of cholesterol homeostasis in liver.…”

“…Although there is very little LXRβ expressed in hepatocytes, literature data diverge concerning the role of LXRs in liver TG accumulation. While some groups report that only LXRα is responsible for liver accumulation of TG (24), others have shown that both LXR isoforms may be responsible for liver lipogenesis (36,38). In LXRα KO mice, lipogenesis in liver is less than in WT mice.…”

“…In LXRα KO mice, lipogenesis in liver is less than in WT mice. However, in LXRα KO mice treated with GW3965, both Srebp1c expression and hepatic TG increased, implying that LXRβ contributes to this hepatic effect (36). Pharmacological activation of LXR with synthetic agonists markedly increases hepatic TG, stimulates very low-density lipoprotein secretion and transiently raises plasma TG levels (1,13,30,48,50).…”

“…Most of the steps of RCT are regulated by LXRs (26,27,33). Both LXRs control the expression of the ATP-binding cassette Abca1 and Abcg1 genes, which play a key role in the RCT from plasma membrane to extracellular acceptors (such as macrophages) and to the liver (9,25,(34)(35)(36). In addition to the ABC transporters that mediate cholesterol efflux, several apolipoproteins (Apo) and lipid-modulating enzymes involved in RCT are also targets of LXR including ApoE in macrophages and adipose tissue (20), and lipoprotein lipase (Lpl) in liver and macrophages (37).…”

Liver X Receptor: A Cardinal Target for Atherosclerosis and Beyond

“…LXR activation also regulates CYP7A1 transcription via LXREs. Impaired CYP7A1 levels have been reported in LXRα −/− mice, resulting in hepatic cholesterol accumulation 29) . Furthermore, activation of the CYP7A1 gene expression is induced by crosstalk between TR-β and LXR-α, thereby controlling cholesterol metabolism 30) .…”