Explore the vast range of titles available.

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.

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.

Electrochemical synthesis can provide more sustainable routes to industrial chemicals 1 – 3 . Electrosynthetic oxidations may often be performed ‘reagent-free’, generating hydrogen (H 2 ) derived from the substrate as the sole by-product at the counter electrode. Electrosynthetic reductions, however, require an external source of electrons. Sacrificial metal anodes are commonly used for small-scale applications 4 , but more sustainable options are needed at larger scale. Anodic water oxidation is an especially appealing option 1 , 5 , 6 , but many reductions require anhydrous, air-free reaction conditions. In such cases, H 2 represents an ideal alternative, motivating the growing interest in the electrochemical hydrogen oxidation reaction (HOR) under non-aqueous conditions 7 – 12 . Here we report a mediated H 2 anode that achieves indirect electrochemical oxidation of H 2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. This quinone-mediated H 2 anode is used to support nickel-catalysed cross-electrophile coupling (XEC), a reaction class gaining widespread adoption in the pharmaceutical industry 13 – 15 . Initial validation of this method in small-scale batch reactions is followed by adaptation to a recirculating flow reactor that enables hectogram-scale synthesis of a pharmaceutical intermediate. The mediated H 2 anode technology disclosed here offers a general strategy to support H 2 -driven electrosynthetic reductions. A quinone-mediated hydrogen anode design shows that hydrogen can be used as the electron source in non-aqueous reductive electrosynthesis, for a more sustainable way to make molecules at larger scale.

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.

The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp³)-CF₃ reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the “fluoride-rebound” mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF₃-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography.

The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation. Inflammation is a normal part of the immune response to infection or tissue damage. However, increased inflammation has been linked to diseases such as obesity, diabetes and atherosclerosis (in which the walls of the arteries become hardened). These same diseases have also been linked to problems with the production or breakdown of fatty molecules, such as cholesterol. Transcription factors are proteins that bind to DNA to control gene expression. A transcription factor called LXR regulates the production and breakdown of cholesterol in response to changing levels of cholesterol in the body. LXR has also been shown to inhibit inflammatory responses, but previous studies suggested that these two actions of LXR are independent of each other. Ito et al. have now challenged these findings by showing that LXR inhibits inflammation via changes in the metabolism of cholesterol and other fatty molecules. The experiments used genetically engineered immune cells, called macrophages, and mice to show that activating LXR causes cholesterol molecules to move between the membranes in a cell. This in turn leads to changes in the signals sent by proteins found at the cell surface, and eventually to a reduction of inflammation responses. Future work will focus on better understanding the link between LXR's effects on metabolism and inflammation in models of human diseases such as diabetes and atherosclerosis.

We have previously shown that mouse atherosclerosis regression involves monocyte-derived (CD68+) cell emigration from plaques and is dependent on the chemokine receptor CCR7. Concurrent with regression, mRNA levels of the gene encoding LXRalpha are increased in plaque CD68+ cells, suggestive of a functional relationship between LXR and CCR7. To extend these results, atherosclerotic Apoe-/- mice sufficient or deficient in CCR7 were treated with an LXR agonist, resulting in a CCR7-dependent decrease in plaque CD68+ cells. To test the requirement for LXR for CCR7-dependent regression, we transplanted aortic arches from atherosclerotic Apoe-/- mice, or from Apoe-/- mice with BM deficiency of LXRalpha or LXRbeta, into WT recipients. Plaques from both LXRalpha and LXRbeta-deficient Apoe-/- mice exhibited impaired regression. In addition, the CD68+ cells displayed reduced emigration and CCR7 expression. Using an immature DC line, we found that LXR agonist treatment increased Ccr7 mRNA levels. This increase was blunted when LXRalpha and LXRbeta levels were reduced by siRNAs. Moreover, LXR agonist treatment of primary human immature DCs resulted in functionally significant upregulation of CCR7. We conclude that LXR is required for maximal effects on plaque CD68+ cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice.

The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 10⁹ neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop have remained indeterminate. Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate both lipid metabolic and inflammatory gene expression. Here, we demonstrate that LXRs contribute to the control of neutrophil homeostasis. Using gain- and loss-of-function models, we found that LXR signaling regulated the efficient clearance of senescent neutrophils by peripheral tissue APCs in a Mer-dependent manner. Furthermore, activation of LXR by engulfed neutrophils directly repressed the IL-23/IL-17/G-CSF granulopoietic cytokine cascade. These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression.

MafB is a transcription factor that induces myelomonocytic differentiation. However, the precise role of MafB in the pathogenic function of macrophages has never been clarified. Here we demonstrate that MafB promotes hyperlipidemic atherosclerosis by suppressing foam-cell apoptosis. Our data show that MafB is predominantly expressed in foam cells found within atherosclerotic lesions, where MafB mediates the oxidized LDL-activated LXR/RXR-induced expression of apoptosis inhibitor of macrophages (AIM). In the absence of MafB, activated LXR/RXR fails to induce the expression of AIM, a protein that is normally responsible for protecting macrophages from apoptosis; thus, Mafb -deficient macrophages are prone to apoptosis. Haematopoietic reconstitution with Mafb -deficient fetal liver cells in recipient LDL receptor-deficient hyperlipidemic mice revealed accelerated foam-cell apoptosis, which subsequently led to the attenuation of the early atherogenic lesion. These findings represent the first evidence that the macrophage-affiliated MafB transcription factor participates in the acceleration of atherogenesis. In the early stages of atherosclerosis, macrophages in the vessel wall convert into foam cells, which promote the rise of atherosclerotic plaques. Here Hamada et al . show that the macrophage transcription factor MafB inhibits foam-cell apoptosis, and that its absence promotes atherosclerosis development in mice.