Cellular cholesterol levels reflect a balance between uptake, efflux and endogenous synthesis. Here we show that the sterol-responsive nuclear receptor LXR helps maintain cholesterol homeostasis not only through promotion of cholesterol efflux, but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (Inducible Degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirusmediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element binding proteins for sterol regulation of cholesterol uptake.

The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. In addition to their function in lipid metabolism, LXRs have also been found to modulate immune and inflammatory responses in macrophages. Synthetic LXR agonists promote cholesterol efflux and inhibit inflammation in vivo and inhibit the development of atherosclerosis in animal models. The ability of LXRs to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in human metabolic disease.Liver X receptor-α (LXRα) and LXRβ (also known as NR1H3 and NR1H2, respectively) were cloned more than a decade ago based on sequence homology with other receptors. LXRs were originally considered "orphan" nuclear receptors, because their natural ligands were unknown (1, 2); however, these receptors were "adopted" following the discovery that metabolites of cholesterol - oxysterols - bind to and activate these receptors at physiological concentrations (2, 3). LXRα is highly expressed in the liver and at lower levels in the adrenal glands, intestine, adipose, macrophages, lung, and kidney, whereas LXRβ is ubiquitously expressed (4). The LXRs are ligand-dependent transcription factors that form permissive heterodimers with the retinoid X receptor (RXR); i.e., the complex can be activated by ligands of either partner (Figure 1). LXR/RXR heterodimers bind to LXR-responsive elements (LXREs) in DNA consisting of direct repeats (DRs) of the core sequence AGGTCA separated by 4 nucleotides (DR-4) (5). Like most other nuclear receptors that form heterodimers with RXR, LXRs reside within the nucleus, bound to cognate LXREs and in complex with corepressors such as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) (6) and nuclear receptor corepressor (N-CoR) (7). In the absence of ligand, these corepressor interactions are maintained and the transcriptional activity of target genes is repressed. Binding of ligand to LXR results in a conformational change that facilitates coactivator-for-corepressor-complex exchange and transcription of target genes (8). Ligand activation of LXRs also inhibits transcription from promoters of certain genes (e.g., proinflammatory cytokines) that do not contain LXREs, a phenomenon referred to as trans-repression.Studies over the last 5 years have established LXRs as key modulators of both lipid metabolism and inflammatory signaling (9). This Review will focus on recent advances in our understanding of the roles of LXRs in physiology and homeostasis as well as the links between LXR action and metabolic diseases such as atherosclerosis.

Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Aβ homeostasis. We report that ApoE plays a previously unappreciated role in facilitating the proteolytic clearance of soluble Aβ from the brain. The endolytic degradation of Aβ peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Aβ degradation extracellularly by insulin degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Aβ degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Aβ degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Aβ load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a novel mechanism through which ApoE facilitates the clearance of Aβ from the brain and suggest that LXR agonists may represent a novel therapy for AD. Alzheimer's disease (AD) is characterized by the accumulation and deposition of Aβ peptides within the brain, leading to the perturbation of synaptic function and neuronal loss that typifies the disease (Tanzi and Bertram, 2005). Genetic analysis of familial forms of AD has established the centrality of APP processing and Aβ production to disease pathogenesis. Aβ peptides are normally produced by neurons in the brain and cleared through efflux into the peripheral Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.