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Purpose To investigate whether the ingestion of olive oil having different phenolic contents influences the expression of blood pressure-related genes, involved in the renin–angiotensin–aldosterone system, in healthy humans. Methods A randomized, double-blind, crossover human trial with 18 healthy subjects, who ingested 25 mL/day of olive oils (1) high (366 mg/kg, HPC) and (2) low (2.7 mg/kg, LPC) in phenolic compounds for 3 weeks, preceded by 2-week washout periods. Determination of selected blood pressure-related gene expression in peripheral blood mononuclear cells (PBMNC) by qPCR, blood pressure and systemic biomarkers. Results HPC decreased systolic blood pressure compared to pre-intervention values and to LPC, and maintained diastolic blood pressure values compared to LPC. HPC decreased ACE and NR1H2 gene expressions compared with pre-intervention values, and IL8RA gene expression compared with LPC. Conclusions The introduction to the diet of an extra-virgin olive oil rich in phenolic compounds modulates the expression of some of the genes related to the renin–angiotensin–aldosterone system. These changes could underlie the decrease in systolic blood pressure observed.

In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of  IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes ( Abcc2 , Abcb11 , and Abcg5/8 ), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC. The authors previously developed a mouse model of parenteral nutrition-associated cholestasis (PNAC) that is dependent on parenteral phytosterols and intestinal injury with DSS. Here they refine the model and show that PNAC pathology is dependent on recruitment of hepatic macrophages and IL-1 signaling.

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.

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.

Uncontrolled regeneration leads to neoplastic transformation 1 , 2 – 3 . The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models 4 , 5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin ( Areg ), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1 , LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis. Liver X receptor drives epithelial Areg -mediated intestinal regeneration, while preventing tumour growth through adaptive immune responses.

The aim of this study was to investigate the mechanisms through which quercetin protects against atherosclerosis (AS) in apoE−/− mice by regulating the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), cluster of differentiation 36 (CD36), peroxisome proliferator-activated receptor γ (PPARγ), liver X receptor α (LXRα) and ATP binding cassette transporter A1 (ABCA1). We established an animal model of high-fat diet induced AS using apoE−/− mice. H&E, Oil Red O and Masson's trichrome staining were performed on aortic sinus and liver tissue sections to evaluate the histopathology, lipid accumulation and collagen deposition, respectively. Filipin staining was performed to detect free cholesterol (FC) in the aortic sinus. ELISA was performed to measure the serum levels of lipids including total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and oxidized low-density lipoprotein (oxLDL), as well as the levels of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10. Western blot analysis was performed to analyze the protein expression levels of PCSK9, CD36, PPARγ, LXRα and ABCA1 in both the aorta and liver tissue. H&E staining revealed the presence of atherosclerotic plaques in the aortic sinus. Oil Red O staining revealed the existence of massive red-stained lipids in the aortic sinus and Masson's trichrome staining revealed decreased collagen fibers and increased plaque instability. Filipin staining revealed that free cholesterol levels in the aorta sinus were increased. In addition, H&E staining suggested hepatocyte structural disorder in the model group, and Oil Red O staining revealed a cytoplasm filled with lipid droplets, which contained a large amount of red-stained lipids. Masson's trichrome staining revealed that the liver tissue of the model group had fewer collagen fibers compared with that of the control group. Moreover, the mice in the model group had higher serum TC, LDL-C, oxLDL, TNF-α and IL-6 levels, and lower IL-10 levels. The protein expression levels of PCSK9 and CD36 were increased, while those of PPARγ, LXRα and ABCA1 were decreased in the aortas and livers of the model group mice. However, treatment with quercetin attenuated all these effects. On the whole, these results demonstrate that quercetin prevents the development of AS in apoE−/− mice by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1.

Abstract Nuclear receptor subfamilies are comprised of members that can have markedly different ligand preferences. The NR1H subfamily contains the farnesoid X receptor (FXR) and liver X receptors (LXR), which regulate myriad metabolic processes, often in a coordinated fashion. As sensors for bile acids and oxysterols, respectively, it is not known what ligand(s) activated the precursor of FXR and LXR. We reconstruct the common FXR/LXR vertebrate ancestor and determine that it responds to neither class of ligands for the extant receptors. Using structural and functional analysis, we identify the set of evolutionary substitutions that recapitulate the shift in ligand preference from the FXR/LXR ancestor to the ancestral vertebrate FXR. We show that the substitutions reshaped the ligand binding pocket to drive this functional shift. Subsequent evolutionary mutations altered the secondary structure of FXR to scaffold the binding pocket and support functional specialization.

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4⁺ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.

Liver x receptor alpha (LXRα) functions as an intracellular cholesterol sensor that regulates lipid metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, elevated cholesterol in the liver may play a critical role in the development of MASH. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH in LXRα mutant mice suggesting that LXRα normally functions to impede the development of liver disease. Liver x receptors (LXRs) regulate lipid metabolism in response to changing cholesterol levels. Here, the authors show that inactivation of LXR signaling leads to the rapid development of metabolic dysfunction-associated steatohepatitis (MASH).

The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRβ from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.