Associations between liver X receptor polymorphisms and blood lipids: A systematic review and meta-analysis.

Genetic susceptibility to dyslipidaemia remains incompletely understood. The liver X receptors (LXRs), members of the nuclear receptor superfamily of ligand dependent transcription factors, are homeostatic regulators of lipid metabolism. Multiple single nucleotide polymorphisms (SNPs)have been identified previously in the coding and regulatory regions of the LXRs. The aim of this systematic review and meta-analysis was to summarise associations between SNPs of LXRs (α and ß isoforms) with blood lipid and lipoprotein traits. Five databases (PubMed, Ovid Embase, Scopus, Web of Science, and the Cochrane Library) were systematically searched for population-based studies that assessed associations between one or more blood lipid/lipoprotein traits and LXR SNPs. Of seventeen articles included in the qualitative synthesis, ten were eligible for meta-analysis. Nine LXRα SNPs and five LXRß SNPs were identified, and the three most studied LXRα SNPs were quantitatively summarised. Carriers of the minor allele A of LXRα rs12221497 (-115G>A) had higher triglyceride levels than GG homozygotes (0.13 mmol/L; 95%CI: [0.03, 0.23], P = 0.01). Heterozygote carriers of LXRα rs2279238 (297C/T) had higher total cholesterol levels (0.12 mmol/L; (95%CI: [0.01, 0.23], P = 0.04) than either CC or TT homozygotes. For LXRα rs11039155 (-6G>A), no significant differences in blood levels of either triglyceride (P = 0.39) or HDL-C (P = 0.98) were detected between genotypes in meta-analyses. In addition, there were no strong associations for other SNPs of LXRα and LXRß. This study provides the evidence of an association between LXRα, but not LXRß, SNPs and blood-lipid traits. Systematic review registration: PROSPERO No. CRD42021246158.

Characterization and prognostic value of LXR splice variants in triple-negative breast cancer.

Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple-negative breast cancer (BCa) relative to other BCa subtypes, driving drug resistance and metastatic gene signatures. The loci encoding LXRα and LXRß produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here, we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRα splice variants was associated with poor prognosis, consistent with a role as an oncogenic driver of triple-negative tumor pathophysiology. Contrary to this was the observation that high expression of truncated LXRα splice variants or any LXRß splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology.

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer.

Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling.

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR's corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease.

Eosinophilic esophagitis (EoE) is a recently recognized esophageal inflammatory disease with clinical manifestations arising from esophageal dysfunction. The etiology of EoE is currently being clarified and food allergy is evolving as the central cornerstone of EoE disease pathogenesis. Given the large number of eosinophils in the esophagus of people with EoE verified by data from murine models EoE is widely considered as the hallmark T-helper type 2 (Th2) disease of the esophagus. It is also known that some eosinophilic inflammation is controlled by other subsets of T cells such as Th9 or Th17 and control is also exerted by type 2 innate lymphoid cells acting together with basophils. In this paper we review results from molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and present in-depth molecular understanding of EoE.

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells.

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery.

Inhibitory effects of quail egg on mast cells degranulation by suppressing PAR2-mediated MAPK and NF-kB activation.

BACKGROUND: Quail egg (QE) has been reported to possess an anti-allergic and anti-inflammatory activity. We have demonstrated that whole QE was able to attenuate the allergic symptoms in food allergy-induced EoE murine model, but whether QE albumen or QE yolk plays a more important role still remains unclear. OBJECTIVE: In this current study, we investigated the suppressive role of QE in mast cell degranulation and cytokine production of the effect phase response. METHOD: A passive cutaneous anaphylaxis (PCA) mouse model was used to confirm the anti-allergic effect of QE. Besides, HMC-1 cell model was used to study its suppressive role in more detail. In this in vitro study, we divided QE into three groups: whole QE, QE albumen, and QE yolk. The effect of QE treatment on mast cell degranulation and intracellular calcium influx was investigated. Moreover, the effect of QE allergy- related mediators, genes, and proteins were also assessed by ELISA, RT-PCR, and western blotting. RESULTS AND DISCUSSION: Our data showed that the extent of mast cell degranulation-mediated ear vascular permeability in IgE-mediated PCA mice treated with whole QE (17 mg/kg) was decreased significantly up to 43.31 ± 0.42% reduction. HMC-1 cell-based immunological assay in vitro indicated that QE, particularly its albumen, acted as a 'mast cell stabilizer'. Under the concentration of 70 µg/mL, QE albumen effectively suppressed the releases of ß-hexosaminidase, histamine, and tryptase, as well as Th2 and pro-inflammatory cytokine production; reached 30 up to 50% reduction. Besides, QE albumen was also able to significantly modulate the upregulation of IL-10 up to 58.30 ± 5.9%. Interestingly, our data indicated that QE yolk still had a significant inhibitory effect on modulating Th2 cytokines in its highest concentration (100 µg/mL), while QE albumen showed no inhibitory effect. Western blot analysis showed QE albumen effectively down-regulated the expressions of calcium-related protein (TRPC1, Orai1, STIM1, PLC-γ and IP3R), facilitated the reduction of PAR-2 and induced the reduction of phosphorylation of JNK, IKKα, p50 and p65 protein expressions. CONCLUSION: As confirmed by PCA and HMC-1 cell-based immunology assay, QE albumen and QE yolk may work together through exerting anti-allergy activity and can be used as a potential anti-allergic nutrient in the future.

Quail egg homogenate alleviates food allergy induced eosinophilic esophagitis like disease through modulating PAR-2 transduction pathway in peanut sensitized mice.

The present pharmacotherapy for eosinophilic esophagitis (EoE) fundamentally depend on inhaled corticosteroids. Despite the fact that oral intake of topical steroids can be successful in restricting EoE-related inflammation, there are concerns with respect to the long term utilization of steroids, especially in kids. In the current research, we assess the effect of quail egg, which is reportedly a known serine protease inhibitor, on symptomatology and immune responses in a peanut-sensitized mouse model of food allergy induced EoE. Daily oral treatment with quail egg attenuated mice symptomatology and immune response. Treatment with quail egg inhibited antigen-prompted increments in mouse tryptase and eosinophil cationic protein (ECP) in serum and eosinophil in inflamed tissues like oesophagus, lung, and digestive system. Quail egg treatment resulted in decreased antibody specific IgE and IgG1 and a variety of inflammatory genes that were abnormally expressed in EoE. Other effects included increased IL-10, decreased PAR-2 activation and NF-kB p65 in inflamed tissues. Our results suggest that quail egg treatment may have therapeutic potential in attenuating the symptoms of food allergy induced EoE like disease through regulating PAR-2 downstream pathway by blocking the activation of the transcription factor NF-kB p65 activity.