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Background and Aims: Fat accumulation results from increased fat absorption and/or defective fat metabolism. Currently, the lipid-sensing nuclear receptor that controls fat utilization in hepatocytes is elusive. Liver X receptor alpha (LXRα) promotes accumulation of lipids through the induction of several lipogenic genes. However, its effect on lipid degradation is open for study. Here, we investigated the inhibitory role of LXRα in autophagy/lipophagy in hepatocytes and the underlying basis., Approach and Results: In LXRα knockout mice fed a high-fat diet, or cell models, LXRα activation suppressed the function of mitochondria by inhibiting autophagy/lipophagy and induced hepatic steatosis. Gene sets associated with "autophagy" were enriched in hepatic transcriptome data. Autophagy flux was markedly augmented in the LXRα knockout mouse liver and primary hepatocytes. Mechanistically, LXRα suppressed autophagy-related 4B cysteine peptidase (ATG4B) and Rab-8B, responsible for autophagosome and -lysosome formation, by inducing let-7a and microRNA (miR)-34a. Chromatin immunoprecipitation assay enabled us to find LXRα as a transcription factor of let-7a and miR-34a. Moreover, 3' untranslated region luciferase assay substantiated the direct inhibitory effects of let-7a and miR-34a on ATG4B and Rab-8B. Consistently, either LXRα activation or the let-7a/miR-34a transfection lowered mitochondrial oxygen consumption rate and mitochondrial transmembrane potential and increased fat levels. In obese animals or nonalcoholic fatty liver disease (NAFLD) patients, let-7a and miR-34a levels were elevated with simultaneous decreases in ATG4B and Rab-8B levels., Conclusions: LXRα inhibits autophagy in hepatocytes through down-regulating ATG4B and Rab-8B by transcriptionally activating microRNA let-7a-2 and microRNA 34a genes and suppresses mitochondrial biogenesis and fuel consumption. This highlights a function of LXRα that culminates in the progression of liver steatosis and steatohepatitis, and the identified targets may be applied for a therapeutic strategy in the treatment of NAFLD., (© 2020 by the American Association for the Study of Liver Diseases.)

Resveratrol (RSV) is a dietary polyphenol with well-documented cardio-protective activity, but its effects on blood cholesterol levels remain to be established. Due to its poor bioavailability, tissue accumulation of RSV is extremely low except for that in the small intestine. In the present study, we aimed to investigate the dose-dependent effects of RSV on blood cholesterol levels and the involvement of small intestine in the cholesterol-lowering impacts of RSV. Mice were administrated with RSV at various doses with high-fat diet (HFD) or high-fat and high-cholesterol diet (HCD) for 12 weeks. The fecal neutral sterol contents were analyzed, and intestinal perfusion test was performed. An enteric barrier model using Caco-2 cells was established. We observed that RSV reduced blood cholesterol levels in a dose-dependent manner in mice fed with HFD or HCD. Further investigation revealed that RSV administration increased the bile acid pool size but did not affect cholesterol consumption or de novo cholesterol synthesis. Interestingly, RSV promoted trans-intestinal cholesterol excretion (TICE) by 2-fold in the intestinal perfusion test. In addition, RSV upregulated the expressions of ATP-binding cassette sub-family G member 5 or 8 (Abcg5/8) and ATP-binding cassette sub-family B member 1a or 1b (Abcb1a/b) by up to 8 times in the duodenum mucosa but not in the liver. RSV also significantly downregulated the expression of intestinal Niemann-Pick C1-Like 1 (Npc1l1). Knock-down of liver X receptor alpha (LXRα) but not Sirt1 by siRNA significantly blocked RSV-induced cholesterol excretion in Caco-2 cells. In conclusion, RSV could decrease circulating cholesterol levels through enhancing TICE and limiting cholesterol absorption via selective activation of intestinal LXRα., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Silicosis, a severe and irreversible form of pulmonary fibrosis (PF) caused by long-term exposure to dust particles in production environments, is the biggest occupational health concern in China and most low-income countries. The transdifferentiation of pulmonary fibroblasts is the terminal event in silicosis, and specific transcription factors (TFs) play a crucial role in this condition. However, the relationship between TF-mediated regulation and silicosis remains unknown. We performed a transcriptomic analysis to elucidate this relationship, and our results revealed that two TFs, EGR2 and BHLHE40, were upregulated and five, i.e., TBX2, NR1H3 (LXRα), NR2F1, PPARG (PPARγ), and EPAS1, were downregulated in activated fibroblasts. Notably, PPARγ and LXRα expression was also decreased in an experimental mouse model of silicosis. The mechanism underlying these changes may involve TGF-β1 secretion from silica-exposed alveolar macrophages, causing PPARγ and LXRα downregulation, which in turn would result in aberrant α-SMA transcription. Our results suggest that LXRα is a potential target for the prevention of silicosis and PF., Competing Interests: Declaration 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 © 2020 Elsevier B.V. All rights reserved.)

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.

Background: Modulators of LXRα are of high pharmacological interest as LXRα regulates fatty acid metabolism, inflammatory processes and cancer. We aim to identify new LXRα modulators and to recognize a distinguishable feature of agonists. Results&methodology: The ligand self-dock and largest-cavity-size searching purposely located two appropriate ligand-binding sites to reach the two aims. One is identifying the new modulators from Maybridge library. 20 new compounds are confirmed by the in vitro reporter gene assay. The other is denoting an agonist by at least one best docking pose having one hydrogen bond to LXRα Helix12 His421. Conclusion: Based on the quality x-ray binding pocket, we can identify new LXRα modulators and distinguish between agonists and antagonists by molecular docking.

Seven unusual new ene-yne hydroquinones ( 1 - 3 , 5 - 8 ), including three rare glycosylated derivatives named pestalotioquinosides A-C ( 6 - 8 ), were obtained from the marine-derived strain SCSIO41403 of the fungus Pestalotiopsis neglecta . Their structures including absolute configurations were elucidated by spectroscopic analysis and induced electronic circular dichroism experiments. In silico molecular docking and in vitro surface plasmon resonance studies showed that pestalotioquinoside C ( 8 ) could act as a liver X receptor alpha (LXRα) modulator. Further study showed that LXR target gene ABCA1 was significantly upregulated by 8 , which revealed 8 as a potential LXRα agonist.

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 7 α -hydroxylase (CYP7a1) and sterol 12 α -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-) 1 β , IL-6, and malondialdehyde; and decreased superoxide dismutase activity in the liver, suggesting inflammatory and oxidative stress. In addition, liver X receptor alpha (LXR α ) 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 LXR α in the liver was inhibited by baicalin. In addition, the LXR α 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 LXR α activity. These findings may provide novel insights for prevention and therapy of gallstones in the clinic., Competing Interests: No conflict of interest exits in the submission of this manuscript. There are no ethical/legal conflicts involved in the article., (Copyright © 2020 Geng Chen and Shuodong Wu.)

The liver X receptor α (LXRα) is a member of the nuclear hormone receptor superfamily that plays an important role in lipid homeostasis. Here we characterize two alternative human LXRα transcripts, designated LXRα2 and LXRα3. All three LXRα isoforms are derived from the same gene via alternative splicing and differential promoter usage. The LXRα2 isoform lacks the first 45 amino acids of LXRα1, and is generated through the use of a novel promoter and first exon. LXRα3 lacks 50 amino acids within the ligand binding domain and is generated through alternative recognition of the 3′-splice site in exon 6. LXRα2 and LXRα3 are expressed at lower levels compared with LXRα1 in most tissues, except that LXRα2 expression is dominant in testis. Both LXRα2 and LXRα3 heterodimerize with the retinoid X receptor and bind to LXR response elements. LXRα2 shows reduced transcriptional activity relative to LXRα1, indicating that the N-terminal domain of LXRα is essential for its full transcriptional activity. LXRα3 is unable to bind ligand and is transcriptionally inactive.These observations outline a previously unrecognized role for the N terminus in LXR function and suggest that the expression of alternative LXRα transcripts in certain biological contexts may impact LXR signaling and lipid metabolism.

OBJECTIVES: Quercetin has been reported to have the activities of antioxidant, anti- inflammatory, anti-virus, anti-cancer and so on. Many studies showed that quercetin could lower blood pressure and improve blood capillary elasticity, and it can also reduce LDL oxidation and prevent atherosclerosis. Although quercetin has been recognized to have the function of preventing atherosclerosis, little is known about its underlying mechanism. In this study, we try to explore whether quercetin up-regulates LXRα-mediated ABCA1 expression. MATERIALS AND METHODS: THP-1 cells were cultured. The expression of ABCA1 and LXRα were detected by real-time PCR and western blot. Cellular cholesterol efflux from THP-1 macrophages was analyzed using liquid scintillation counting assays. RESULTS: Real-time PCR and Western blot showed quercetin increased the expression of ABCA1 and LXRα at both the mRNA and protein levels in a concentration-dependent and time-dependent manner in THP-1 macrophages. Liquid scintillation counting assays indicated quercetin increased the cholesterol efflux and decreased the cellular cholesterol content. Furthermore, the expression of LXRα was decreased after THP-1 macrophage transfected with LXRα siRNA. Meanwhile, the expression of ABCA1 was also recovered after incubated with the combination of LXRα siRNA and quercetin compared with quercetin alone. CONCLUSIONS: Quercetin could increase ABCA1 expression and cholesterol efflux through LXRα pathway to eventually promote RCT in the THP-1 macrophage. [ABSTRACT FROM AUTHOR]

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., Competing Interests: None

Liver X receptor-[alpha] mediates cholesterol efflux in glomerular mesangial cells. Am J Physiol Renal Physiol 287: F886-F895, 2004. First published July 27, 2004; doi:10.1152/ajprenal.00123.2004.--Lipid-mediated injury plays an important role in the pathogenesis of many renal diseases including diabetic nephropathy. Liver X receptor-[alpha] (LXR[alpha]) is an intracellular sterol sensor that regulates expression of genes controlling cholesterol absorption, excretion, catabolism, and cellular efflux. The present study was aimed at examining the role of LXR[alpha] in cholesterol metabolism in glomerular mesangial cells. A 1,561-bp fragment of full-length rabbit LXR cDNA was cloned. The deduced protein sequence exhibited 92.4 and 89.2% identity to human and mouse LXR[alpha], respectively. Tissue distribution studies showed that rabbit LXR[alpha] was expressed in the liver, spleen, and kidney. In situ hybridization and RT-PCR assays further indicated that LXR[alpha] mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXR[alpha], rabbits were treated with thiazolidinedione (TZD) peroxisome proliferator-activated receptor--[gamma] (PPAR[gamma]) agonists, which have been previously shown to enhance LXR[alpha] expression via PPAR[gamma] and increase cholesterol efflux in macrophages. The results showed that glomerular LXR[alpha] expression was markedly induced by TZDs. In cultured rabbit mesangial cells, LXR[alpha] mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXR[alpha] agonist, TO-901317, significantly increased basal and apolipoprotein AI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXR[alpha] target gene, ATP-binding cassette transporter A1 (ABCA1). In conclusion, LXR[alpha] is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates cholesterol efflux via ABCA1. These data suggest that LXR[alpha] may be a potential therapeutic target for treating lipid-related renal glomerular disease. glomeruli; ATP-binding cassette transporter A1

In the nematode Caenorhabditis elegans, nuclear hormone receptor DAF-12 regulates the decision to go into a resistant dauer diapause, in which the worm exhibits a decreased rate of aging. Using sequence similarity searches, we previously identified the liver X receptor alpha (LXR[alpha]) as one of the human nuclear hormone receptors the protein sequence of which is most similar to C. elegans DAF-12. Here, we studied whether variation in the gene encoding LXR[alpha] associates with human life span. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we genotyped four polymorphisms spanning the gene coding for LXR[alpha] (NRIH3) and tagged four common haplotypes. Among 563 participants, haplotype 2 associated with reduced mortality during the 7-year follow-up (hazard ratio 0.78; p = .015), predominantly caused by reduced mortality from infectious disease (hazard ratio 0.31; p = .023). Haplotype 2 also associated with higher levels of plasma apolipoprotein E, a target gene of the LXR[alpha] (p = .018), and higher levels of triglycerides (p = .041). Genetic variation in the gene coding for the LXR[alpha] (NR1H3) associates with human life span.

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. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXR α . Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXR α transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXR α -induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXR α by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXR α and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXR α and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXR α and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXR α and PXR signaling., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 Tsai-Sung Tai et al.)

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.