Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3b-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7a-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists. Nuclear liver X receptors (LXRs) are involved in the control of cholesterol and lipid metabolism. LXRa (NR1H3) and LXRb (NR1H2) are sterol sensors that bind oxysterols to act as a transcriptional switch for the coordinated regulation of genes involved in cellular cholesterol homeostasis, cholesterol transport, catabolism, and absorption (1). In peripheral cells such as macrophages, LXRs are likely to coordinate a physiological response to cholesterol loading by regulating the transcription of several genes involved in cholesterol efflux and catabolism, including ATP-binding cassette (ABC)A1 and G1 (2-6).

Key Words: farnesoid X receptor Ⅲ vascular calcification Ⅲ chronic kidney disease V ascular calcification is very common in subjects with chronic kidney disease (CKD) and is an independent predictor of cardiovascular mortality. [1][2][3][4][5][6] Accumulation of calcium-phosphate complex in vascular wall decreases aortic elasticity and flexibility, which impairs cardiovascular hemodynamics, resulting in substantial morbidity and mortality. This process was considered to be passive. However, recent studies have shown that it is a highly orchestrated process that entrains a repertoire of transcription factors including msh homeo box (Msx)2, 7 osterix, 6 and runt-related transcription factor (Runx)2 8 and involves the activation of an osteogenic program that recapitulates the molecular fingerprints seen in bone formation. Vascular calcified cells express many bonerelated proteins, including alkaline phosphatase (ALP) and type I collagen (COL1A1). [5][6][7] In addition, in vitro and in vivo models of vascular calcification have implicated a variety of factors in the pathogenesis of calcification, including osteoprotegrin, osteopontin, osteocalcin (OCL), matrix ␥-carboxyglutamic acid protein (MGP), phosphate, inflammatory cytokines, lipids and reactive oxygen species. 6 Despite these insights, it is still not fully known how vascular calcification is regulated and potential treatment modalities for this disease remain elusive.In addition to their detergent effects on dietary lipids and fat-soluble vitamins absorption, bile acids exert several biological functions via a number of nuclear and plasma membrane receptors, including farnesoid X receptor (FXR), TGR5, vitamin D receptor, and pregnane X receptor. 8 -11 Thus, bile acids are signaling molecules governing not only bile acid synthesis, conjugation and transport, but also lipid, carbohydrate and energy metabolism. FXR is a member of the nuclear receptor family of transcription factors activated by bile acids, the most potent endogenous ligand being chenodeoxycholic acid. 12,13 FXR is highly expressed in tissues in which bile acids are present at high concentration, such as liver, kidney and intestine. Analysis of FXR function using genetically deficient mice and synthetic agonists has established the important role of this receptor in the control of bile acid, lipid and carbohydrate metabolism. 14 -16 Recent studies have also shown that functional FXR is expressed in vascular cells, including vascular smooth muscle cells and endothelial cells. [17][18][19] FXR expression is also observed in the atherosclerotic lesions of human aorta. 17 FXR directly and indirectly regulates the transcription of genes involved in lipoprotein metabolism such as SR-BI, apolipoprotein (Apo)AI, ApoCII, ApoCIII, phospholipid transfer protein, sterol regulatory element binding protein (SREBP)-1c, and very-low-density lipoprotein receptor. 8,12,15,16 Studies using FXR Ϫ/Ϫ mice have shown that FXR deficiency increases plasma triglycerides, cholesterol and high-density lipoprotein choles...

Aims Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model. Methods and results Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1−/− mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1−/− splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1−/− spleen displayed anomalous Treg and TH cell differentiation. NEAT1−/− bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1−/− BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1−/− bone marrow and blood. NEAT1−/− mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals. Conclusion The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1−/− mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.

Genome-wide association studies (GWAS) have proven a fundamental tool to identify common variants associated to complex traits, thus contributing to unveil the genetic components of human disease. Besides, the advent of GWAS contributed to expose unexpected findings that urged to redefine the framework of population genetics. First, loci identified by GWAS had small effect sizes and could only explain a fraction of the predicted heritability of the traits under study. Second, the majority of GWAS hits mapped within non-coding regions (such as intergenic or intronic regions) where new functional RNA species (such as lncRNAs or circRNAs) have started to emerge. Bigger cohorts, meta-analysis and technical improvements in genotyping allowed identification of an increased number of genetic variants associated to coronary artery disease (CAD) and cardiometabolic traits. The challenge remains to infer causal mechanisms by which these variants influence cardiovascular disease development. A tendency to assign potential causal variants preferentially to coding genes close to lead variants contributed to disregard the role of non-coding elements. In recent years, in parallel to an increased knowledge of the non-coding genome, new studies started to characterize disease-associated variants located within non-coding RNA regions. The upcoming of databases integrating single-nucleotide polymorphisms (SNPs) and non-coding RNAs together with novel technologies will hopefully facilitate the discovery of causal non-coding variants associated to disease. This review attempts to summarize the current knowledge of genetic variation within non-coding regions with a focus on long non-coding RNAs that have widespread impact in cardiometabolic diseases.