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Key Points The liver X receptors (LXRs) are sterol-sensitive transcription factors that regulate cholesterol homeostasis. LXRs control the expression of genes that are linked to lipid synthesis, transport and excretion in many tissues. LXRs are crucial regulators of the reverse cholesterol transport pathway and are important determinants of whole-body cholesterol content. Pharmacological activation of LXRs inhibits the development of atherosclerosis in animal models. Subtype-selective LXR agonists and tissue-selective agonists are promising strategies for the development of targeted modulators of lipid metabolism. Alterations in LXR-dependent gene expression and cholesterol metabolism have been associated with the development of neurological diseases, including Alzheimer's disease. LXR is a promising therapeutic target but the development of novel drugs faces many challenges, including undesirable hepatic side effects. The liver X receptors (LXRs) are key regulators of lipid homeostasis. Here, the authors highlight tissue-specific aspects of LXR function with a focus on the liver, intestine and brain, and discuss the implications of recent advances in the understanding of LXR activity for drug development. The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.

Key Points Nuclear receptors have an integral role in cellular processes, translating metabolic, hormonal and nutritional signals to changes in gene expression. Liver X receptor (LXR) and farnesoid X receptor (FXR) form a heterodimer with retinoid X receptor (RXR) and mediate changes in gene expression following activation by their natural ligands, oxysterols and bile acids, respectively. LXRs regulate whole-body cholesterol homeostasis by controlling the uptake, transport and excretion of cholesterol in a tissue-selective manner. In addition to having effects on cholesterol regulation, LXR activation has been shown to mediate changes in lipid and carbohydrate metabolism in the liver and in extra-hepatic tissues such as adipose, skeletal muscle and the pancreas. FXR is a central regulator of bile acid homeostasis, controlling key steps in the production and enterohepatic circulation of bile acids. FXR mediates its effects on bile acid metabolism via direct induction of target genes and by indirect repression via induction of small heterodimer partner (SHP). Recent studies have demonstrated an additional role for FXR in the regulation of lipid and glucose metabolism. Alterations to the above-mentioned pathways are associated with obesity, diabetes and atherosclerosis. LXR and FXR act on mulitple pathways involved in these metabolic diseases, making these nuclear receptors attractive targets for pharmaceutical intervention on multiple levels. Nuclear receptors integrate hormonal and nutritional signals, resulting in changes to key metabolic pathways within the body. The liver X receptor (LXR) and the farnesoid X receptor (FXR), which are activated by oxysterols and bile acids, respectively, have essential roles in the regulation of cholesterol and bile acid metabolism but are also key integrators of sterol, fatty acid and glucose metabolism. Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.

In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.

Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome. Systemic homeostasis is finely orchestrated by the action of several organs and molecules. Here Priest et al. provide a comprehensive review that highlights the inter-organ communication complexity in metabolic regulation.

Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X 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, adenovirus-mediated 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 nuclear receptors known as PPARs and LXRs are lipid-activated transcription factors that have emerged as key regulators of lipid metabolism and inflammation. PPARs and LXRs are activated by non-esterified fatty acids and cholesterol metabolites, respectively, and both exert positive and negative control over the expression of a range of metabolic and inflammatory genes. The ability of these nuclear receptors to integrate metabolic and inflammatory signalling makes them attractive targets for intervention in human metabolic diseases, such as atherosclerosis and type 2 diabetes, as well as for the modulation of inflammation and immune responses.

Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.

The conserved long noncoding RNA MeXis has anti-atherosclerotic effects in mice by acting with the nuclear hormone receptor LXR in macrophages to promote cholesterol efflux. Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type–specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1 , which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type–selective actions of nuclear receptors in physiology and disease.

The activation of lipid X receptors (LXRs) in mouse liver not only promotes cholesterol efflux but also inhibits cholesterol synthesis simultaneously; this is mediated by the lipid-responsive long non-coding RNA LeXis , which is induced by a Western diet and orchestrates crosstalk between LXRs and the cholesterol biosynthetic pathway. Modulation of cholesterol metabolism Liver X receptors (LXRs) and sterol regulatory element-binding proteins (SREBPs) are transcription factors that act as key regulators of cellular and systemic cholesterol homeostasis, controlling cholesterol efflux and cholesterol production, respectively. This study shows that the activation of LXRs in mouse liver not only promotes cholesterol efflux but also inhibits cholesterol synthesis. This activation is mediated by the lipid-responsive long non-coding RNA LeXis , which is induced by a Western diet and orchestrates crosstalk between LXRs and the cholesterol biosynthetic pathway. Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux 1 , facilitates cholesterol esterification by promoting fatty acid synthesis 2 , and inhibits cholesterol uptake by the low-density lipoprotein receptor 3 . The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways are incompletely understood. Here we show that ligand activation of LXRs in mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.

Six patients with severe hypertriglyceridemia (chylomicronemia) were found to have autoantibodies against a capillary endothelial-cell protein (GPIHBP1) that transports lipoprotein lipase to the capillary lumen. A protein in the lymphocyte antigen 6 (Ly6) superfamily, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), is expressed on the surface of capillary endothelial cells. GPIHBP1 binds lipoprotein lipase in the interstitial spaces (where the lipase is secreted by myocytes and adipocytes) and shuttles it to its site of action in the capillary lumen. 1 , 2 In patients with GPIHBP1 deficiency, lipoprotein lipase is mislocalized in the interstitial spaces and never reaches the capillary lumen. The absence of intraluminal lipoprotein lipase prevents the lipolytic processing of triglyceride-rich lipoproteins and results in severe hypertriglyceridemia (chylomicronemia, defined as a triglyceride level of . . .