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Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus. Show less

Biochanin A (BCA), a dietary isoflavone extracted from red clover and cabbage, has been shown to antagonize hypertension and myocardial ischemia/reperfusion injury. However, very little is known about its role in atherogenesis. The aim of this study was to observe the effects of BCA on atherosclerosis and explore the underlying mechanisms. Our results showed that administration of BCA promoted reverse cholesterol transport (RCT), improved plasma lipid profile, and decreased serum proinflammatory cytokine levels and atherosclerotic lesion area in apoE Show less

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 Show less

Notwithstanding the researches on biomarkers and targeted therapies in renal cell carcinomas (RCC) have made progress in the last decades, the application of the biomarkers and targeted therapy agents for RCC in clinic are restricted because of their limitation or side effects. Liver X receptors (LXRs) and the NLRP3 inflammasome have been the research hotspots in recent years. In our study, we integrated bioinformatics analysis, molecular biology experiments and biological function experiments to study the roles of LXRα and the NLRP3 inflammasome in RCC. The study demonstrated that the elevated LXRα expression is correlated with a poor prognosis in RCC. Furthermore, our study revealed the expression levels and roles of the NLRP3 inflammasome in RCC for the first time. This research demonstrated that LXRα could promote the metastasis of RCC cells by suppressing the expression of the NLRP3 inflammasome. In Brief, LXRα had the possibility to be a novel diagnostic and prognostic biomarker and therapeutic target in renal cell cancer and LXRα could regulate the metastasis of renal cell cancer via NLRP3 inflammamsome. Show less

Pancreatic β-cells are sensitive to fluctuations in cholesterol content, which can damage the insulin secretion pathway, contributing to the aetiology of type 2 diabetes mellitus. Cholesterol efflux to (apo)lipoproteins, via ATP-binding cassette (ABC) transporter A1 (ABCA1), can prevent intracellular cholesterol accumulation; in some peripheral cells, ABCA1-dependent efflux is enhanced by promotion of cholesterol trafficking to, and generation of Liver X receptor (LXR) ligands by, mitochondrial sterol 27-hydroxylase (Cyp27A1 (cytochrome P450 27 A1/sterol 27-hydroxylase)) and its redox partners, adrenodoxin (ADX) and ADX reductase (ADXR). Despite this, the roles of mitochondrial cholesterol trafficking (steroidogenic acute regulatory protein [StAR] and 18-kDa translocator protein [TSPO]) and metabolising proteins in insulin-secreting cells remain wholly uncharacterised. Here, we demonstrate an increase in pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, but not ADX or StAR, in obese ( Show less

PDZK1 (NHERF3) interacts with membrane proteins whereby modulating their spatial arrangement, membrane stability, and function. One of the membrane proteins shown to be stabilized by interaction with PDZK1 is the HDL-receptor SR-BI (SCARB1). Testing the influence of TO 901317, a known activator of liver X receptor alpha (LXRα, NR1H3) which is a central regulator of the lipid homeostasis, Grefhorst et al. reported in 2012 that administration of TO 901317 did not affect PDZK1 expression and reduced the amount of SR-BI protein in mouse liver. Considering that TO 901317 also activates the xenosensor pregnane X receptor (PXR, NR1I2), it was aim of this study to further investigate the influence of LXRα and PXR activation on transcription of PDZK1. First, we tested the transactivation of PDZK1 by LXRα or PXR in cell-based reporter gene assays comparing the effect of prototypical ligands to that of TO 901317. Ligand mediated activation of LXRα increased, while that of PXR lowered luciferase activity. Further, we located the most likely binding site for LXRα and PXR on the PDZK1 promoter between -85 bp and -54 bp. The transcriptional regulation by LXRα was further supported showing enhanced mRNA expression of PDZK1 in HepG2 cells treated with the selective LXRα-agonist GW3965, while treatment with TO 901317 reduced the protein amount of PDZK1. Taken together, we provide evidence that both LXRα and PXR are transcriptional regulators of PDZK1 supporting the previous notion that the scaffold protein is part of cholesterol homeostasis and drug metabolism. Show less

Liver X receptors (LXRs) α (NR1H3) and β (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies such as dyslipidemia, atherosclerosis, diabetes and/or cancers. These receptors are known to be activated by specific oxysterol compounds. The screening for LXR-specific ligands is a challenging process: indeed, these molecules should present a specificity towards each LXR-isoform. Because some natural products have significant effects in the regulation of the LXR-regulated homeostasis and are enriched in flavonoids, we have decided to test in cell culture the effects of 4 selected flavonoids (galangin, quercetin, apigenin and naringenin) on the modulation of LXR activity using double-hybrid experiments. In silico, molecular docking suggests specific binding pattern between agonistic and antagonistic molecules. Altogether, these results allow a better understanding of the ligand binding pocket of LXRα/β. They also improve our knowledge about flavonoid mechanism of action, allowing the selection and development of better LXR selective ligands. Show less

Liver X receptors (LXRs) are ligand-dependent transcription factors activated by cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and cholesterol transport in many tissues. Two different isoforms, LXRα and LXRβ, have been well characterized in liver, adipocytes, macrophages, and intestinal epithelium among others, but their contribution to cholesterol and fatty acid efflux in the lactating mammary epithelium is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets upregulated sharply early in lactation compared with midpregnancy. LXRα is the primary isoform, and its protein levels increase throughout lactation in MECs. The LXR agonist GW3965 markedly induced several genes involved in cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk cholesterol percentage and induced sterol regulatory element-binding protein 1c (Srebp1c) and ATP-binding cassette transporter a7 (Abca7) expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation. Show less

Liver X receptors (LXRs) are members of the nuclear receptor family, including the LXRα (NR1H3) and LXRβ (NR1H2) subtypes, which are related to the metabolism of glucose and cholesterol and possess anti-inflammatory functions. Mounting evidence has linked LXRs to the inhibition of cell proliferation in a variety of cancers. We revealed a differential distribution for NR1H3, but not for NR1H2, in colorectal cancer and adjacent normal tissues. We found that NR1H3 enhanced the inhibitory action of GW3965, an agonist of LXRs, on the proliferation of colorectal cancer cells. Upregulation of NR1H3 enhanced the inhibition of cell proliferation by GW3965 while silencing of NR1H3 attenuated the inhibitory effect of GW3965 on cell proliferation. Bioinformatic prediction and luciferase assays showed that NR1H3 was able to inhibit the activity of the epidermal growth factor receptor (EGFR) promoter. Moreover, we demonstrated that activation of NR1H3 inhibited the growth of transplanted tumors in an animal experiment, with the inhibition accompanied by downregulation of EGFR. Our findings suggest that NR1H3 controls cell proliferation by affecting EGFR promoter activity. The high expression of EGFR was due to the downregulation of NR1H3 which is a novel molecular mechanism in the development of colorectal cancer. Show less

Accumulation of cholesterol is a well-known feature in cancer. Preclinical studies suggest the contribution of various cholesterol regulators in CRC. However, their clinical relevance remains poorly understood. The aim of the present study is to evaluate the expression of these modulators in CRC and elucidate their diagnostic and prognostic value. mRNA levels of HMGCR, SREBF2, NR1H3 and NR1H2 were downregulated in tumors in local and TCGA cohort. The expression of LDLR, ABCA1 and SCARB1 was not consistent in the two cohorts. Western Blot analysis showed the increased levels of LDLR and reduced levels of LXR in early stage patients. Tumoral SREBP2 levels were enhanced in early stage whereas decreased in late stage. The individual expression of HMGCR, SREBF2, NR1H3 and NR1H2 did not have the potential to be used as independent prognostic marker, however, the combined expression of these genes associated with poor clinical outcome independent of lymph node metastasis, distant metastasis and advanced stage. This work sheds light on deregulation of cholesterol uptake and efflux pathways and provides novel leads in the development of biomarkers and therapeutic regimens that can detect and target CRC at initial stages. Show less

A prior study in bovine mammary (MACT) cells indicated that long-chain fatty acids (LCFA) C16:0 and C18:0, but not unsaturated LCFA, control transcription of milk fat-related genes partly via the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, in that study, the activation of PPARγ by LCFA was not demonstrated but only inferred. Prior data support a lower response of PPARγ to agonists in goat mammary cells compared to bovine mammary cells. The present study aimed to examine the hypothesis that LCFA alter the mRNA abundance of lipogenic genes in goat mammary epithelial cells (GMEC) at least in part via PPARγ. Triplicate cultures of GMEC were treated with a PPARγ agonist (rosiglitazone), a PPARγ inhibitor (GW9662), several LCFA (C16:0, C18:0, Show less

Fructose has become a major constituent of our modern diet and is implicated as an underlying cause in the development of metabolic diseases. The fructose transporter GLUT5 (SLC2A5) is required for intestinal fructose absorption. GLUT5 expression is induced in the intestine and skeletal muscle of type 2 diabetes (T2D) patients and in certain cancers that are dependent on fructose metabolism, indicating that modulation of GLUT5 levels could have potential in the treatment of these diseases. Using an unbiased screen for transcriptional control of the human GLUT5 promoter we identified a strong and specific regulation by liver X receptor α (LXRα, NR1H3). Using promoter truncations and site-directed mutagenesis we identified a functional LXR response element (LXRE) in the human GLUT5 promoter, located at -385 bp relative to the transcriptional start site (TSS). Finally, mice treated with LXR agonist T0901317 showed an increase in Glut5 mRNA and protein levels in duodenum and adipose tissue, underscoring the in vivo relevance of its regulation by LXR. Together, our findings show that LXRα regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXRα might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer. Show less

Atherosclerosis is characterized by the accumulation of excess cholesterol in plaques. Reverse cholesterol transport (RCT) plays a key role in the removal of cholesterol. In the present study, we examined the effect of thioredoxin-1 (Trx-1) on RCT and explored the underlying mechanism. We found that Trx-1 promoted RCT in vivo, as did T0901317, a known liver X receptor (LXR) ligand. T0901317 also inhibited the development of atherosclerotic plaques but promoted liver steatosis. Furthermore, Trx-1 promoted macrophage cholesterol efflux to apoAI in vitro. Mechanistically, Trx-1 promoted nuclear translocation of LXRα and induced the expression of ATP-binding cassette transporter A1 (ABCA1). Apolipoprotein E knockout (apoE-/-) mice fed an atherogenic diet were daily injected intraperitoneally with saline or Trx-1 (0.33 mg/kg). Trx-1 treatment significantly inhibited the development of atherosclerosis and induced the expression of ABCA1 in macrophages retrieved from apoE-/- mice. Moreover, the liver steatosis was attenuated by Trx-1. Overall, we demonstrated that Trx-1 promotes RCT by upregulating ABCA1 expression through induction of nuclear translocation of LXRα, and protects liver from steatosis. Show less

Our study aimed to investigate the expression of NR1H3 in endometrial carcinoma, its effect on the proliferation of endometrial carcinoma cells in vitro, and the underlying mechanism of this effect. Immunohistochemistry of paraffin-embedded, sectioned specimens and of a tissue microarray was conducted to estimate the expression of NR1H3 (liver X receptors α: LXRα) and NR1H2 (liver X receptors β: LXRβ) in endometrial carcinoma tissues. The subcellular localization of NR1H3 in the endometrial carcinoma cell line Ishikawa was determined by immunofluorescence. An agonist of NR1H3, TO901317, was then administered to activate the expression of NR1H3, and cell viability and cell-cycle progression were investigated through MTT and flow cytometric assays, respectively. The gene and protein expression levels of NR1H3, cyclin D1 (CCND1), and cyclin E (CCNE) in cells pretreated with different concentrations of TO901317 for different periods of time were also detected by real-time RT-PCR and Western blot, respectively. The results showed that, in contrast to NR1H2, which was expressed at low levels in endometrial tissues, NR1H3 was upregulated in endometrial adenocarcinoma tissues compared to levels in normal endometrial tissues and endometrial polyps. Moreover, NR1H3 was mainly expressed in the cytoplasm of Ishikawa cells. TO901317 significantly decreased cell viability and arrested the cell cycle in Ishikawa cells in a dose- and time-dependent manner. Furthermore, the administration of TO901317 not only promoted the expression of NR1H3 but also inhibited the expression of CCND1 and CCNE in Ishikawa cells. We demonstrated that NR1H3 is upregulated in endometrial adenocarcinoma and that it inhibits cell viability by inhibiting the expression of CCND1 and CCNE in endometrial carcinoma cells. Our study indicates that NR1H3 may play a role in the development of endometrial cancer and may emerge as a promising therapeutic target. Show less

Niacin is currently the most effective drug that increases HDL‑C levels. Apolipoprotein M (ApoM) in humans is mainly found in plasma high‑density lipoprotein (HDL). Little is known about the role played by niacin in ApoM expression. In this study, the effects of niacin on ApoM expression were assessed as well as the associated mechanism. Human liver cancer cell line HepG2 was treated with niacin alone or with liver X receptor‑α (LXRα) inhibitor at multiple concentrations. The mRNA and protein expression of ApoM were assessed by qRT‑PCR and western blotting. Specific LXRα shRNA was transfected into HepG2 cells to further evaluate the regulatory effects of LXRα on ApoM. An in vivo model was also established to investigate the LXRα inhibitor on the mouse ApoM levels. The comparisons among groups were evaluated using one‑way ANOVA and Student‑Newman‑Keuls test. It was revealed that in HepG2 cells, niacin dose‑dependently increased ApoM gene and protein expression levels. Niacin‑induced upregulation of ApoM was attenuated by an LXRα inhibitor or LXRα shRNA, indicating that LXRα mediated this effect. Moreover, niacin treatment resulted in increased LXRα mRNA levels, in vivo and in vitro; niacin treatment resulted in increased ApoM gene and protein expression levels in mice. In conclusion, niacin upregulates ApoM expression by increasing LXRα expression in vivo and in vitro. Show less

Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity. Show less

Liver X receptors are members of the nuclear receptor superfamily of transcription factors. The LXR genes (NR1H2 and NR1H3) encode for two different proteins referred to as LXRα and LXRβ. Each LXR presents diverse tissue distribution but similar target DNA-binding elements and ligands. Both LXRs act as relevant transcriptional regulators of cholesterol metabolism in many tissues. Additionally, LXRs participate in innate immunity and inflammation. Therefore, in order to understand the molecular requirements that operate in LXR-dependent transcription, it is important to decipher LXR genomic binding properties. We have recently performed genome-wide binding analysis of LXR proteins. In this method paper, we describe a detailed computational protocol primarily based on HOMER software package for the analysis of ChIP-seq data. Show less

The selection of active compounds for the quality evaluation of traditional Chinese medicine (TCM), specifically complex formulas, remains a challenge for researchers, as components selected as indexes usually have no clear relation with the therapeutic effects of interest. As a suggested resolution, quality control markers (Q-markers) showed good perspective for discriminating numerous compounds found for specific efficacies. In the presented study, the components of the Yinlan (YL) capsule, a TCM patent formula comprising four ingredients, were evaluated and selected for their lipid regulatory effects using principles for Q-marker selection. The mechanism of TCM therapeutic effects involves several pathways and targets that combine to become an integrated action in the body. Therefore, it is assumed that specific compounds in YL should have good affinity for related targets and obvious effects (both up- and downregulating). Thus, a series of experiments, including cytobiology, animal-based pharmacodynamics, computer-assisted drug design, conventional content determination and pharmacokinetics, would be helpful for the selection and final confirmation of Q-markers. The capsule was first administered to Wistar mice fed a high-fat diet and tested for their triglycerides (TG) and total cholesterol (TC) values to evaluate the effectiveness of YL. Then, liver tissue was extracted for gene expression. According to the results, the compounds in YL with good affiliation were selected and determined using UHPLC-MS-MS, and those with adequate results in the capsule were chosen as Q-marker candidates. Finally, pharmacokinetics research was performed; the candidates with desirable metabolite and bioavailability parameters were confirmed as Q-markers of YL. YL capsule was capable of lowering TG and TC levels. For target selection, the expression of LXR mRNA increased significantly at all three tested dosages. Downstream genes, such as LCAT, CYP7A1, and ABCA1, and intestinal FXR mRNA also showed significant increases in expression. For screening of the Q-marker candidates, 5 compounds were selected according to abovementioned results. The pharmacokinetics research demonstrated that the rats exploited lupeol and ginsenoside Rb3 in a desirable pattern with adequate bioavailability, which confirmed their roles as lipid regulatory Q-markers. The YL capsule was demonstrated to have obvious lipid regulatory effects, which are mainly exerted by targeting LXR and its related pathway. Lupeol and ginsenoside Rb3 were validated as Q-markers that represent the anti-hyperlipidemia activity of the capsule. Show less

Cigarette smoke extract (CSE) contains many toxicants and may derange the physiological processes, such as cholesterol metabolism. We examined the impact of CSE on transcriptional regulation mediated peroxisome proliferator-activated receptors (PPARs) and its interaction with cofactors to elucidate differences in the molecular mechanism between CSE and other agonists of PPARs. We constructed several mutant PPARs (mPPARs) with amino acid substitution in the ligand-binding domain, which according to the molecular modeling, may affect the binding of agonists. In transient expression assays, each wild-type peroxisome proliferator-activated receptor (PPAR) mediated transcription stimulated by CSE was faintly yet significantly elevated compared to the control. The CSE-induced transcriptional activation was abolished in the H323A, H323Y, S342A, and H449A mPPARγs, although the activation elevated by pioglitazone was reserved. In the mPPARγ with Y473A and mPPARβ/δs with H286Y and Y436A, the pioglitazone-induced or L165041-activated transcriptional elevations were decreased and were lower than that of CSE-induced stimulation. These results suggested that CSE activated both mutant PPARs to be selectively different from those ligands. Mammalian two-hybrid assay illustrated that CSE could mildly recruit SRC1 or GRIP1 to the wild-type PPARγ. Representative ingredients, such as acrolein and crotonaldehyde present in CSE, could stimulate PPAR isoforms even at the toxicological concentrations and might possibly contribute to stimulatory effects. CSE mildly regulates the cholesterol metabolism-related genes, such as low density lipoprotein (LDL) receptor and Liver X receptor (LXR)β. In conclusion, these CSE effects the nuclear hormone receptors and their cofactors thereby disturbing metabolic phenomena. Therefore, CSE might be involved in cholesterol metabolism. Show less

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. Show less

To investigate the mechanism of the combined effects of chlorogenic acid (CGA) and caffeine on lipid metabolism in high-fat diet-induced obese mice, eighty female ICR mice were randomly divided into eight groups and fed with a high-fat diet with/without CGA and/or caffeine for 14 weeks. The combination of CGA and caffeine effectively decreased body weight gain, intraperitoneal adipose tissue weight, serum LDL-c, FFA, TC, TG, leptin, IL-6 concentrations, and hepatic TG and TC levels and increased the serum adiponectin level. The CGA and caffeine combination also promoted the phosphorylation of AMPKα, inhibited the expressions of transcriptional regulators (SREBP-1c and LXRα), and decreased the expressions of FAS and HMGR. Besides, the expressions of ACO, ATGL and HSL were increased by the CGA and caffeine combinations. The results indicated that the combination of CGA and caffeine had anti-obesity effects and regulated lipid metabolism in high-fat diet-induced obese mice via the AMPKα-LXRα/SREBP-1c signaling pathway. Thus, chronic CGA and caffeine intakes may be potent for preventing obesity. Show less

Maternal undernutrition programs fetal energy homeostasis and increases the risk of metabolic disorders later in life. This study aimed to identify the signs of hepatic metabolic programming in utero and during the juvenile phase after intrauterine undernutrition during midgestation. Fifty-three pregnant goats were assigned to the control (100% of the maintenance requirement) or restricted (60% of the maintenance requirement from day 45 to day 100 of midgestation and realimentation thereafter) group to compare hepatic energy metabolism in the fetuses (day 100 of gestation) and kids (postnatal day 90). Undernutrition increased the glucagon concentration and hepatic hexokinase activity, decreased the body weight, liver weight and hepatic expression of Maternal undernutrition affects the metabolic status in a sex- and stage-specific manner by changing the metabolic profile, expression of genes involved in glucose homeostasis and enzyme activities in the liver of the fetuses. The changes in the hormone levels in the male fetuses and kids, but not the female offspring, represent a potential sign of metabolic programming. Show less

Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1β-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA. Show less

There is scarce data on CASR associations with dyslipidemia. We investigated in hemodialysis (HD) patients whether CASR single nucleotide polymorphisms (SNPs) rs7652589 and rs1801725 have associations with dyslipidemia and show epistatic interactions with SNPs of the energy homeostasis-associated gene (ENHO), retinoid X receptor α gene (RXRA), and liver X receptor α gene (LXRA). The study included 1208 HD subjects. For diagnosis of dyslipidemia, both K/DOQI criteria and atherogenic index ≥3.8 were used. CASR rs1801725 was genotyped by TaqMan SNP Genotyping Assay, other SNPs - by high-resolution melting curve analysis or polymerase chain reaction-restriction fragment length polymorphism, as appropriate. Relative transcript levels of CASR, ENHO, RXRA, and LXRA were measured in peripheral blood mononuclear cells. The occurrence of dyslipidemic phenotypes concerning tested polymorphisms was compared using models of inheritance. Haplotypes were estimated using the Haploview 4.2 software. Epistatic interactions between tested SNPs were analyzed using the logistic regression and epistasis option in the PLINK software. Rs7652589 indicated a greater probability of atherogenic dyslipidemia in the dominant inheritance model (OR 1.4, 95%CI 1.0-2.0, P = 0.026), principally because of increased triglyceride (TG) levels. The rs1801725 variant allele was associated with a decreased probability of dyslipidemia characterized by non-HDL-cholesterol ≥130 mg/dL and TG ≥200 mg/dL (OR 0.6, 0.4-0.9, P = 0.012). There were no epistatic interactions between CASR and RXRA, LXRA, and ENHO regarding dyslipidemia. Both rs7652589 and rs1801725 SNPs were not in linkage disequilibrium (D' = 0.091, r CASR polymorphisms (rs7652589, rs1801725) are associated with dyslipidemia in HD patients. CASR correlates with RXRA, LXRA, and ENHO at the transcript level. Further investigations may elucidate whether other CASR SNPs contribute to associations shown in this study. Show less

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as 'cholesterol sensors' to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences. Show less

In bovine mammary tissue and cells, liver X receptor (LXR) regulates lipid synthesis mainly via transactivation of the transcription factor sterol regulatory element binding protein 1 (SREBP1). In the present work, we investigated the role of LXR in controlling lipid synthesis via transactivation of SREBP1 in goat primary mammary cells (GMEC). The GMEC were treated with a synthetic agonist of LXR, T0901317, and transactivation and transcription of SREBP1, expression of lipogenic genes, and fatty acid profiling and triacylglycerol (TAG) content of the cells were measured. A mild increase in the mRNA expression level of LXRα (NR1H3) was observed following treatment with different concentrations of T0901317, and a dose-dependent increase in mRNA and transactivation of SREBP1 was detected. Activation of LXR resulted in a significant increase in the mRNA expression of most of the measured genes related to de novo synthesis, desaturation, and transport of fatty acids; TAG synthesis; and transcription regulators. Compared with the control, total content of cellular TAG increased by more than 20% with T0901317 treatment. Furthermore, addition of T0901317 increased the proportion of unsaturated fatty acids (e.g., C16:1, C18:1, C20:1, and C22:1), and decreased the proportion of saturated fatty acids (e.g., C16:0, C18:0, C20:0, and C22:0). These results provide evidence that LXR regulates the expression and activity of SREBP1. Our results indicated that LXR participate in regulating the transcription of genes involved in milk fat synthesis in GMEC in an SREBP1-dependent fashion. Show less

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target. Show less