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Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for inducing cardiovascular diseases. However, the effects and mechanisms of action of exserolides on hyperlipidemia are not known. The aim of this study is to investigate whether the marine fungus Setosphaeria sp.-derived exserolides (compounds I, J, E, and F) exert lipid-lowering effects via improving reverse cholesterol transport (RCT) in vitro. RAW264.7 macrophages and HepG2 cells were used to establish lipid-laden models, and the levels of intracellular lipids and RCT-related proteins were determined by assay kits and Western blotting, respectively. We observed that exserolides (at a 5 μM concentration) significantly decreased intracellular cholesterol and triglyceride levels in oxidized low-density lipoprotein-laden RAW264.7 cells and markedly improved [3H]-cholesterol efflux. Among the four tested compounds, exserolide J increased the protein levels of ATP-binding cassette transporter A1, peroxisome proliferator-activated receptor α (PPARα), and liver X receptor α (LXRα). Furthermore, treatment with exserolides significantly decreased oleic acid-laden lipid accumulation in HepG2 hepatocytes. Mechanistically, exserolides enhance PPARα protein levels; furthermore, compound J increases cholesterol 7 alpha-hydroxylase A1 and LXRα protein levels. Molecular docking revealed that exserolides, particularly compound J, can interact with PPARα and LXRα proteins. These data suggest that the terminal carboxyl group of compound J plays a key role in lowering lipid levels by stimulating LXRα and PPARα proteins. In conclusion, compound J exhibits powerful lipid-lowering effects in vitro. However, its hypolipidemic effects in vivo should be investigated in the future.

Abstract In Alzheimer’s disease (AD) more than 50% of the patients are affected by capillary cerebral amyloid-angiopathy (capCAA), which is characterized by localized hypoxia, neuro-inflammation and loss of blood-brain barrier (BBB) function. Moreover, AD patients with or without capCAA display increased vessel number, indicating a reactivation of the angiogenic program. The molecular mechanism(s) responsible for BBB dysfunction and angiogenesis in capCAA is still unclear, preventing a full understanding of disease pathophysiology. The Liver X receptor (LXR) family, consisting of LXRα and LXRβ, was reported to inhibit angiogenesis and particularly LXRα was shown to secure BBB stability, suggesting a major role in vascular function. In this study, we unravel the regulatory mechanism exerted by LXRα to preserve BBB integrity in human brain endothelial cells (BECs) and investigate its role during pathological conditions. We report that LXRα ensures BECs identity via constitutive inhibition of the transcription factor SNAI2. Accordingly, deletion of brain endothelial LXRα is associated with impaired DLL4-NOTCH signalling, a critical signalling pathway involved in vessel sprouting. A similar response was observed when BECs were exposed to hypoxia, with concomitant LXRα decrease and SNAI2 increase. In support of our cell-based observations, we report a general increase in vascular SNAI2 in the occipital cortex of AD patients with and without capCAA. Importantly, SNAI2 strongly associated with vascular amyloid-beta deposition and angiopoietin-like 4, a marker for hypoxia. In hypoxic capCAA vessels, the expression of LXRα may decrease leading to an increased expression of SNAI2, and consequently BECs de-differentiation and sprouting. Our findings indicate that LXRα is essential for BECs identity, thereby securing BBB stability and preventing aberrant angiogenesis. These results uncover a novel molecular pathway essential for BBB identity and vascular homeostasis providing new insights on the vascular pathology affecting AD patients.

The present study aimed to determine the association of adrenergic receptor beta-3 (ADRB3) rs4994 T>C and liver X receptor alpha (LXR-α) rs12221497 G>A polymorphism with metabolic syndrome (Met S) and the related traits in Pakistanis. Patients of Met S were recruited from the Endocrinology and Diabetic Clinic of Sheikh Zayed Hospital Lahore, over the time span of 6 months from July to December 2016. Single-nucleotide polymorphism (SNP) of ADRB3 was determined by restriction fragment length polymorphism and of LXR-α by amplification refractory mutation system polymerase chain reaction. The frequency of TT variant of ADRB3 T>C in Met S was 69 (34.5%) and in controls 89 (44.5%), frequency of TC 103 (51.5%) and 96 (48%), and of CC 28 (14%) and 15 (7.5%), respectively. In the recessive model (CC: TT + TC), CC genotype was found to be associated with the increased risk of Met S (P = 0.027; odds ratio [OR] = 2.09; confidence interval [CI] =1.08–4.03) and the association remained significant after controlling for the confounders such as age and sex. The frequency of GG variant of LXR-α G>A in Met S was 35 (17.5%) and in controls 15 (7.5%), GA 129 (64.5%) and 137 (68.5%), and AA 36 (18%) and 48 (24%), respectively. In the recessive model (GG: GA + AA), GG genotype was found to be associated with the increased risk of Met S (P = 0.004; OR = 2.52; CI = 1.33–4.80) and the association remained significant after controlling for the confounders such as age and sex. It was concluded that SNP of ADRB3 (190 T>C) and LXR-α (−115 G>A) were associated with the risk of Met S and might increase the susceptibility to the obesity-related traits.

Liver X Receptor Alpha (LXRα) is a nuclear receptor that play a crucial role in regulating of gene involvedin lipid metabolism. The aim of this research was to identify polymorphisms and association of LXRα gene with charateristic of carcass, meat quality and fatty acid composition in ducks using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). A total sample of 98 Cihateup ducks consisted of 57 females and 41 males with age 12 weeks were used in this study. Product size is 661 bp amplicons. The genotype genes frequencies in CC, GC and GG were 0.21, 0.55 and 0.23 respectively. The chi-square test revealed that LXRα gene (g.3575 C>G) in exon 2 was in Hardy-Weinberg equilibrium. A SNP of LXRα gene in region g.3575 C>G was significantly associated (P

BACKGROUND: microRNAs play pivotal roles in metabolism and other aspects of cell biology. microRNA-33 and liver X receptor (LXR) affect lipid metabolism and cholesterol trafficking. In this study, we evaluated effects of co-administration of miR-33 inhibitor and LXR activator on LXR-α and adenosine triphosphate-binding cassette transporter A1 (ABCA1) expression in mice liver. METHODS: Twenty-four mice were randomly allocated into four groups (n = 6). Group 1 mice received standard chow diet without any treatment, group 2 received 30 mg/kg/48 hour LXR agonist (T0901317), group 3 received 1 mg/kg/48 hour in vivo locked nucleic acids (LNA) anti-miR-33 and group 4 received both T0901317 and in vivo LNA anti-miR-33. All treatments were administrated through intraperitoneal injection (IP). After 7 days and at the end of the study, mice were sacrificed, liver tissues were excised and blood samples were collected. LXR-α and ABCA1 genes and protein expression were quantified by real-time polymerase chain reaction (PCR) and western blotting, respectively. RESULTS: LXR activation caused LXR-α and ABCA1 mRNA (P < 0.050) and protein elevation as compared to control (P < 0.001). miR-33 inhibition attenuates T0901317 effect on LXR-α expression in group IV. Co-administration of T0901317 and anti-miR-33 remarkably elevated high-density lipoprotein cholesterol (HDL-C) levels, compared to control group (P = 0.001). Separate administration of T0901317 and anti-miR-33 also elevated HDL-C levels (P < 0.010). CONCLUSION: Co-administration of T0901317 and anti-miR-33 can be considered as a good therapeutic alternative for atherosclerosis because miR-33 inhibition reduced lipogenic effects of LXR-α activator and also helps LXR-α agonist to increase reverse cholesterol transport (RCT) and also HDL-C as antiatherogenic effects.

Background: A group of adenosine triphosphate binding cassette transporter (ABCs) including ABCA1, ABCG1, ABCG4, ABCG5 and, ABCG8 induce cholesterol efflux from the cell and thereby are target genes in prevention and treatment of atherosclerosis. ABCA1, ABCG5 and, ABCG8 genes are activated by liver X receptor (LXR) and liver receptor homolog-1 (LRH-1) that play essential roles in metabolic processes related to cholesterol metabolism. Oxysterols that are derivatives of cholesterol, or by-products of cholesterol biosynthesis that contain additional oxygen functions as hydroxyl, carbonyl, or epoxide groups, are LXR ligands; thus, LXR and LRH-1 are cell cholesterol sensors. LXRs are ligand-activated transcription factors that regulate the metabolism of several genes related to lipids, cholesterol, and bile acids and their activity is effective in the prevention of atherosclerosis. The aim of this study was to investigate the effects of 12 weeks high-intensity interval training (HIT) and low-intensity continuous training (LIT) after high-fat diet on LXRα gene expression in male Wistar rats. Methods: This experimental study was done in two phases of obesity induction and training exercises. The rats after 13 weeks of high-fat diet (40% lipid) assigned in 3 groups of control (with high-fat diet) (N=5), HIT training (with high-fat diet) (N=5) and LIT training (with high fat diet) (N=5). For statistical analysis, the one-way ANOVA and the least significant difference (LSD) post-hoc tests were used for comparison of groups. The duration of exercises was 12 weeks (5 sessions per week). The research was done in the Sport Sciences Research Institute of Shahid Mirghani, Gorgan City, Iran, from December 2018 to July 2019. Results: Results showed significant differences of LXRα gene expression between groups (P≤0.05), as highest levels of LXRα gene expression were in HIT group and its lowest levels were in control group. Conclusion: In summary, results showed that 12 weeks high-intensity interval training (HIT) and low-intensity continuous training after 13 weeks high-fat diet increased LXRα gene expression that may be a predictive mechanism for atherosclerosis especially in obese persons. Also, HIT training was more effective in elevation of LXRα gene expression.

Context Ganoderma lucidum (Leyss.ex Fr.) Karst (Ganodermataceae) is a fungus that has been used in traditional Chinese medicine. Objective This is the first investigation of the lipid-lowering and anti-atherosclerotic effects of Ganoderma lucidum spore ethanol extract (EEG) in hyperlipidemic rabbits. Materials and methods Fifty-four Japanese rabbits were randomly divided into six groups (n = 9): control, model, atorvastatin and three EEG groups (6, 24 and 96 mg/kg/day, p.o.). Control group was administered a normal diet and other groups were administered a high-fat diet to induce hyperlipidaemia and atherosclerosis for 14 weeks. During this time, lipid profiles were recorded; lipid testing and histopathological examination of aorta and liver were conducted. LXRα and its downstream genes expression in the liver and small intestine were examined. The effect of EEG on macrophage cholesterol efflux and ABCA1/G1 expression was observed under silenced LXRα expression. Results EEG reduced serum cholesterol (20.33 ± 3.62 mmol/L vs 34.56 ± 8.27 mmol/L for the model group) and LDL-C, reduced the area of arterial plaques (24.8 ± 10% vs 53.9 ± 15.2% for the model group) and Intima/Medium thickness ratio, increased faecal bile acid content, upregulated LXRα, CYP7A1, ABCA1/G1, ABCG5/G8 expression in the liver, small intestine and macrophages. After silencing LXRα in macrophages, the ability of EEG to promote cholesterol efflux was inhibited. Discussion and conclusion EEG exert lipid-lowering and anti-atherosclerotic effects via upregulating expression of LXRα and downstream genes associated with reverse cholesterol transport and metabolism. However, whether PPARα/γ are involved in the up-regulation of LXR expression by EEG remains to be elucidated.

This study was aimed at investigating the effect of baicalin on experimental cholesterol gallstones in mice. The mouse gallstone model was induced by feeding with a lithogenic diet, and cholesterol stones were found in the gallbladder. The lithogenic diet caused elevation of triglycerides, cholesterol, and low-density lipoprotein concentrations and descent of high-density lipoprotein concentration in serum. Hyperplasia and inflammatory infiltration were observed in the gallbladder wall of lithogenic diet-fed mice. We also found the increase of cholesterol content and the decrease of bile acid in bile. Real-time PCR and western blot results demonstrated that the expression levels of two enzymes (cholesterol 7α-hydroxylase (CYP7a1) and sterol 12α-hydroxylase (CYP8b1)) to catalyze the synthesis of bile acid from cholesterol were decreased and that two cholesterol transporters (ATP-binding cassette transporter G5/G8 (ABCG5/8)) were increased in the liver of lithogenic diet-fed mice. The lithogenic diet also led to enhanced activity of alanine aminotransferase and aspartate aminotransferase in serum; increased concentrations of tumor necrosis factor-α, interleukin- (IL-) 1β, IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXRα) was increased in the liver. After gavage of baicalin, the lithogenic diet-induced gallstones, hyperlipidemia, gallbladder hyperplasia, inflammation, and oxidative stress in liver and cholesterol metabolism disorders were all alleviated to some degree. The expression of LXRα in the liver was inhibited by baicalin. In addition, the LXRα agonist T0901317 aggravated lithogenic diet-induced harmful symptoms in mice, including the increase of gallstone formation, hyperlipidemia, hepatic injury, inflammation, and oxidative stress. In conclusion, we demonstrated that baicalin played a protective role in a lithogenic diet-induced gallstone mouse model, which may be mediated by inhibition of LXRα activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic.

Background: Liver X receptor alpha (LXRA) plays important role in cholesterol and lipid homeostasis and lipid metabolism; moreover, it has been investigated as a candidate gene in a number of conditions, including onset and progression of atherosclerosis. We hypothesized that the LXRA gene rs2279238 polymorphism may be associated with the onset and progression of carotid atherosclerosis in the Slovenian cohort., Methods: 783 unrelated Slovenian patients were included in this cross-sectional case-control study: 308 patients in the group of cases with severe internal carotid artery (ICA) stenosis (>75 %) and 475 patients with hemodynamically insignificant ICA stenosis (<50 %) in the control group. Medical records were used to acquire patient laboratory and clinical data. The TaqMan SNP Genotyping assay was used to genotype the rs2279238 polymorphism., Results: Between the case and control groups, we identified a statistically significant variation in genotype distribution (p = 0.04), but not in allele frequency (p = 0.13) of the LXRA gene polymorphism rs2279238. The results, also show that there is a statistically significant association (p = 0.04) between the two genetic models (codominant and recessive) of the LXRA gene rs2279238 polymorphism and carotid atherosclerosis., Conclusion: In the Slovenian cohort, we found a significant association between the TT genotype of rs2279238 and advanced carotid artery disease, suggesting that this polymorphism might be a genetic risk factor for ICA atherosclerosis., (Copyright © 2022. Published by Elsevier B.V.)

Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction occurring independently of a recognized cause such as hypertension or coronary artery disease. Liver X receptor [alpha] (LXR[alpha]), a subtype of ligand-activated transcription factors LXRs, has been considered as a potential pharmacological target in the pathogenesis of cardiovascular and metabolic diseases. However, the potential mechanism of how LXR[alpha] is regulated in cardiomyocytes is still unclear. This study investigated the effect of activating LXR[alpha] with GW3965 on cardiomyocyte apoptosis and its upstream regulator in glucose-induced H9C2 cells. Our data indicated that GW3965 up-regulated the expression of LXR[alpha], inhibited cardiomyocyte apoptosis, and altered the apoptosis-related proteins in glucose-induced H9C2 cells. In addition, GW3965 restored the mitochondrial membrane potential level and decreased the ROS production induced by glucose. Moreover, LXR[alpha] was confirmed as a direct target of microRNA-1 (miR-1) that was involved in cardiomyocyte apoptosis of DCM, and overexpression of miR-1 abrogated the inhibiting effect of GW3965 on glucose-induced apoptosis in H9C2 cells. This study highlights an important role of LXR[alpha] in the development of DCM and brings new insights into the complex mechanisms involved in the pathogenesis of DCM. Key words: diabetic cardiomyopathy, liver X receptor [alpha], microRNA-1, apoptosis, reactive oxygen species. La cardiomyopathie diabétique (CMD) est définie comme un dysfonctionnement ventriculaire qui survient indépendamment d'une cause reconnue comme l'hypertension ou la coronaropathie. Le récepteur nucléaire LXR[alpha] (<>), un sous-type des facteurs de transcription activés par les ligands LXR, a été considéré comme cible pharmacologique potentielle dans la pathogenèse des maladies cardiovasculaires et métaboliques. Cependant, le possible mécanisme par lequel le LXR[alpha] est régulé dans les cardiomyocytes n'est toujours pas clair. Cette étude visait à examiner l'effet de l'activation du LXR[alpha] par le GW3965 sur l'apoptose des cardiomyocytes et sur ses régulateurs en amont chez les cellules H9C2 traitées au glucose. Les données ont révélé que le GW3965 régulait à la hausse l'expression du LXR[alpha], inhibait l'apoptose des cardiomyocytes et modifiait l'expression des protéines liées à l'apoptose chez les cellules H9C2 traitées au glucose. De plus, le GW3965 rétablissait le potentiel membranaire mitochondrial et diminuait la production de DRO induite par le glucose. En outre, puisque le LXR[alpha] s'est avéré une cible directe du microARN-1 (miR-1) impliqué dans l'apoptose des cardiomyocytes dans la CMD, la surexpression de miR-1 abolissait l'effet inhibiteur du GW3965 sur l'apoptose induite par le glucose chez les cellules H9C2. Cette étude souligne le rôle important du LXR[alpha] dans le développement de la CMD et apporte de nouvelles connaissances pour mieux comprendre les mécanismes complexes impliqués dans la pathogenèse de la CMD. [Traduit par la Rédaction] Mots-clés: cardiomyopathie diabétique, LXR [alpha], microARN-1, apoptose, dérivés réactifs de l'oxygène., Introduction There is a growing amount of data showing that patients with diabetes mellitus (DM) display a high risk of developing heart failure, independent from other risk factors such as [...]

Background: Liver x receptor α (LXRα) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Oxysterols (endogenous oxidized cholesterol derivatives) are the most potent endogenous LXRα-agonist. LXRα has a direct impact on several members of drug transporter superfamilies; ATP-binding cassette (ABC) and solute linked carrier (SLC)., Objective: The current study aimed to investigate the effect of LXRα-activation by either endogenous oxysterols or a synthetic LXRα-agonist (LXRa) such as TO901317 on hepatic and cardiac gene expression of ABCC10 and SLC17A5 drug transporters in an experimentally hypercholesterolemic rat model., Methods: 48 male rats were divided randomly into four groups (n = 12); control group rats received vehicle; hypercholesterolemic group (HCH group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks; (LXRa group) rats were fed standard pellet chow for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg; (HCH + LXRa group) rats received diet contain 2.5% cholesterol &deoxycholic acid for 8 weeks, then a single dose of LXRa was administered (IP) at a dose of 10 mg/kg., Results: Our findings revealed that hypercholesterolemia and LXRa significantly activated LXRα to varying degrees in both hepatic and cardiac tissues with subsequent alteration of LXRα and ABCC10 gene expression. Whereas, SLC17A5 gene expression was primarily affected by elevated serum cholesterol level and unmediated via LXRα-activation., Conclusions: Accordingly, it was concluded that ABCC10 is a specific LXRα-target gene and that LXRα autoregulates its own expression in rats., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dysfunction of the blood-brain barrier (BBB) contributes significantly to the pathogenesis of several neuroinflammatory diseases, including multiple sclerosis (MS). Potential players that regulate BBB function are the liver X receptors (LXRs), which are ligand activated transcription factors comprising two isoforms, LXRα, and LXRβ. However, the role of LXRα and LXRβ in regulating BBB (dys)function during neuroinflammation remains unclear, as well as their individual involvement. Therefore, the goal of the present study is to unravel whether LXR isoforms have different roles in regulating BBB function under neuroinflammatory conditions. We demonstrate that LXRα, and not LXRβ, is essential to maintain barrier integrity in vitro. Specific knockout of LXRα in brain endothelial cells resulted in a more permeable barrier with reduced expression of tight junctions. Additionally, the observed dysfunction was accompanied by increased endothelial inflammation, as detected by enhanced expression of vascular cell adhesion molecule (VCAM-1) and increased transendothelial migration of monocytes toward inflammatory stimuli. To unravel the importance of LXRα in BBB function in vivo, we made use of the experimental autoimmune encephalomyelitis (EAE) MS mouse model. Induction of EAE in a constitutive LXRα knockout mouse and in an endothelial specific LXRα knockout mouse resulted in a more severe disease score in these animals. This was accompanied by higher numbers of infiltrating leukocytes, increased endothelial VCAM-1 expression, and decreased expression of the tight junction molecule claudin-5. Together, this study reveals that LXRα is indispensable for maintaining BBB integrity and its immune quiescence. Targeting the LXRα isoform may help in the development of novel therapeutic strategies to prevent BBB dysfunction, and thereby neuroinflammatory disorders.

Nuclear receptors are a superfamily of transcription factors that regulate gene transcription and intracellular function. They have a key role in various biological processes. Liver X receptors (LXR) mainly play role in lipid metabolism, cholesterol synthesis, glucose homeostasis, and inflammation whereas retinoid X receptor alpha (RXRa) plays important role in inflammation and immunity. In this study, Plantago holosteum, P. major subsp. major, P. lagopus, P. scabra, and Scutellaria salviifolia were selected for further investigation due to their anti-inflammatory activities. For this purpose, liver x receptor alpha (LXRa) and retinoid x receptor alpha (RXRa) agonist activity of the extracts was determined through luciferase reporter gene assay on HEK293 cells at a concentration of 100 µg/ml. P. holosteum, P. major subsp. major, P. lagopus, and P. scabra extracts showed weak LXRa agonist activity with the fold values in a range of 0.95-1.39. P. major showed the highest agonist activity among tested Plantago species. For LXRa agonist activity, S. salviifolia extract had a fold value of 2.37 which was comparable to the positive control T09011317 at 10 nM concentration. Results for RXRa agonist activity found to be similar to LXRa for all extracts. S. salviifolia showed the highest RXRa agonist activity with a fold value of 1.62. Results suggested that Scutellaria species, which are used as traditional medicine especially in eastern Asia due to its anti-inflammatory effects, might show this effect due to LXRa activation. [ABSTRACT FROM AUTHOR]

Liver X Receptor Alpha (LXRa) is a nuclear receptor that play a crucial role in regulating of gene involvedin lipid metabolism. The aim of this research was to identify polymorphisms and association of LXRa gene with charateristic of carcass, meat quality and fatty acid composition in ducks using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). A total sample of 98 Cihateup ducks consisted of 57 females and 41 males with age 12 weeks were used in this study. Product size is 661 bp amplicons. The genotype genes frequencies in CC, GC and GG were 0.21, 0.55 and 0.23 respectively. The chi-square test revealed that LXRa gene (g.3575 C>G) in exon 2 was in Hardy-Weinberg equilibrium. A SNP of LXRa gene in region g.3575 C>G was significantly associated (P<0.05) with duck meat quality and fatty acid content. Several parameters have significant affect (P <0. 05) on meat quality in the breast meat weight, carcass percentage and head percentage, while associated fatty acids were saturated fatty acids (SFA) such as palimitic acid (C16:0); γ-and unsaturated fatty acids (UFA) such as linolenic acid (C18:3n3); cis 11 eicosenoic acid (C20:1) and 11.14 cis-eicosedenoic acid (C20:2). In could be concluded that LXRa gene might be useful as genetic markers to select and produce meat with desirable unsaturated fatty acids. [ABSTRACT FROM AUTHOR]