OBJECTIVES: The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily, and LXR-β is an important receptor for cholesterol content in brain cells. LXR-β/retinoic X receptor (RXR-α)/ATP binding cassette transporter A1 (ABCA1) cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer's disease (AD). LXR agonist TO901317 can affect the accumulation of β- amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice. However, the molecular mechanism is not clarified in detail. This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet, and to explore its possible mechanism from the perspective of cholesterol metabolism. METHODS: Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups, 6 mice in each group: a control group (fed with normal diet), a cholesterol rich diet (CRD) group, a TO901317 group (fed with CRD combined with TO901317), and a GSK2033 group (fed with CRD combined with TO901317 and LXR antagonist GSK2033). The mice were fed with pellet feed made of high cholesterol feed, mixed with lard, egg yolk powder, and cod liver oil twice a day. TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%. The drugs were given to the mice daily through gastric tube according to their body weight. Meanwhile, the mice in the drug group were fed with high cholesterol diet . After feeding for 3 months, Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group. The contents of TC, LDL, and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry, and the differences among the groups were compared. The expression of Aβ₄₂ in the brain of AD mice was detected by ELISA. Western blotting was used to detect the protein levels of LXR-β, RXR-α, ABCA1, and Caveolin-1 in the brain of each group. RESULTS: Morris water maze results showed that the times, distance and the duration of mice crossing the platform in the CRD group were significantly decreased compared with the control group (all P<0.05), while these three figures in TO901317 group were significantly increased compared with the CRD group (all P<0.05). Compared with the TO901317 group, there was a decrease of these figures in the GSK2033 group (all P<0.05). The serum TC and LDL levels in the CRD group were significantly higher than those in the control group, while HDL levels were significantly lower (all P<0.001). The figures of the TC and LDL contents level in the TO901317 group were lower than those in the CRD group, while HDL levels were higher (all P<0.001). Compared with TO901317 group, the contents of the TC and LDL in GSK2033 group were significantly increased, while HDL content was significantly decreased (all P<0.001). ELISA results showed that the production of Aβ₄₂ peptides in the brain of CRD group was the highest while the content in the TO901317 group was significantly decreased (P<0.001), which was the lowest among the groups. The figure in the control group was close to the GSK2033 group. Western blotting results showed that the protein levels of LXR-β, RXR-α, and ABCA1 in the CRD group were significantly decreased compared with the control group, but the protein level of Caveolin-1 was increased (all P<0.01). After TO901317 treatment, the protein levels of LXR-β, RXR-α and ABCA1 were significantly increased, while the protein level of Caveolin-1 was decreased partially (all P<0.001). In the GSK2033 group, the effect of TO901317 on AD mice was partially reversed by GSK2033. Compared to TO901317 group, the protein levels of LXR-β, RXR-α, and ABCA1 showed a decrease trend, while the protein level of Caveolin-1 showed an increase state (all P<0.05). CONCLUSIONS High cholesterol diet leads to severer spatial exploration, learning and memory impairment in transgenic AD mice, while the LXR agonist TO901317 attenuates this effect. The mechanism may be that TO901317 promotes cholesterol efflux by activating LXR-β/RXR-α/ABCA1 transmembrane transport system, reduces the expression of Caveolin-1, improves the composition of lipid raft, and ultimately reduces the production of Aβ₄₂ in the brain.
Male ; Animals ; Mice ; Liver X Receptors/metabolism* ; Mice, Transgenic ; Alzheimer Disease/genetics* ; Caveolin 1/metabolism* ; Hydrocarbons, Fluorinated/pharmacology* ; Cognition ; Amyloid beta-Peptides/metabolism* ; Cholesterol

OBJECTIVE: To examine the expression of liver X receptor-β (LXR-β) in human gastric cancer tissue, and to explore the effect of GW3965, an agonist of LXRs, on proliferation of gastric cancer cell line SGC-7901.
 METHODS: The immunohistochemical assay was used to detect the expression of LXR-β, activating transcription factor 4 (ATF4) in gastric cancer tissues and the corresponding pericarcinoma tissues in 114 patients. Real-time quantitative PCR and Western blot were used to determine mRNA and protein levels of ATF4 and ATP-binding cassette 1 (ABCA1), one of the downstream target genes of LXRs, in SGC-7901 cells with or without GW3965 treatment. Cell counting kit-8 (CCK-8) assay was performed to detect cell proliferation. The expression of ATF4 was silenced by short hairpin RNA (shRNA).
 RESULTS: The expressions of LXR-β and ATF-4 were obviously down-regulated in the gastric cancer tissues than that in the corresponding pericarcinoma tissues (both P<0.05). Compared with the control cells, GW3965 treatment inhibited proliferation of SGC-7901 cells and up-regulated ATF4 and ABCA1 expressions (both P<0.05). Knockdown of ATF4 can reverse the antiproliferative effect of GW3965 on SGC-7901 cells.
 CONCLUSION The expression of LXR-β is decreased in human gastric cancer tissues, and activation of LXRs by GW3965 could inhibit the proliferation of SGC-7901 cells via ATF4.
Activating Transcription Factor 4 ; genetics ; metabolism ; Benzoates ; pharmacology ; Benzylamines ; pharmacology ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; Liver X Receptors ; Orphan Nuclear Receptors ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; Stomach Neoplasms ; pathology ; Up-Regulation

OBJECTIVETo use a rat model of nonalcoholic liver disease (NAFLD) to observe effects of the peroxisome proliferator-activated receptor-a (PPAR-a) agonist fenofibrate on hepatic steatosis in nonalcoholic fatty liver and to investigate the underlying mechanism.

METHODSSixty-six Sprague-Dawley rats were given adaptive feeding for 1 week and then randomly allocated into the following three groups: unmodeled control (group C,n =18), untreated NAFLD model (group M, n =24), and fenofibrate-treated NAFLD model (group F, n =24).Group C rats were given a normal diet, while group M and group F rats were given a high-fat diet. After model establishment, the group F rats were treated with fenofibrate (10 mg/kg/d, intraperitoneal) and the group C and group M rats were given sham-treatment with cosolvent (5 mL/kg/d, intraperitoneal). At the end of treatment weeks 4, 6 and 8, one-third of rats in each group were euthanized.Liver tissues were assessed by hematoxylin-eosin (HE) staining to determine level of steatosis and inflammaion activity, and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling to measure changes in hepatocyte apoptosis index. Changes in expression levels of the PPAR-a receptor and apoptosis factors (bcl-2, bax and caspase-3) were assessed by reverse transcription-PCR and immunohistochemistry.

RESULTSThe NAFLD modeled rats showed appropriate induction of hepatic steatosis, hepatic inflammation, and hepatocyte apoptosis. Compared to the group M rats, the group F rats showed lower expression of PPAR-and bcl-2 and higher expression of bax and caspase-3 at both the mRNA and protein level.

CONCLUSIONFenofibrate can ameliorate hepatic steatosis in an experimental rat model of NAFLD, and the mechanism may be associated with inhibition of hepatocyte apoptosis.

Animals ; Apoptosis ; Caspase 3 ; metabolism ; Diet, High-Fat ; Fenofibrate ; pharmacology ; Hepatocytes ; drug effects ; Non-alcoholic Fatty Liver Disease ; pathology ; Peroxisome Proliferator-Activated Receptors ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein ; metabolism

No abstract available.
Antibodies, Monoclonal, Murine-Derived/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; B-Cell-Specific Activator Protein/metabolism ; Bone Marrow/metabolism/*pathology ; Cyclophosphamide/therapeutic use ; Doxorubicin/therapeutic use ; Endoscopy, Digestive System ; Female ; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ; Genetic Loci ; Humans ; Liver/metabolism/pathology ; Lymphocytes/cytology/immunology ; Lymphoma, Large B-Cell, Diffuse/complications/*diagnosis/drug therapy ; Lymphoma, T-Cell, Peripheral/complications/*diagnosis/drug therapy ; Middle Aged ; Prednisone/therapeutic use ; Receptors, Antigen, T-Cell, gamma-delta/genetics ; Tomography, X-Ray Computed ; Vincristine/therapeutic use

BACKGROUNDStatin therapy has affected glucose homoeostasis of type 2 diabetes patients, which could be related with bile acids metabolism. Whether bile acid metabolism and the expression of farnesoid X receptor (FXR), liver X receptor-α (LXR-α) and sterol regulatory element-binding protein (Srebp)-1c is regulated by hyperglycemia, or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.

METHODSForty male Wistar rats were randomly divided into four groups: normal control rats, insulin resistance rats, diabetic model rats, and the late simvastatin induced diabetic rats. Normal control rats were fed with standard diet, others were fed with high-fat diet. Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin (STZ). The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats. Characteristics of fasting blood glucose (FPG), lipid files and total bile acids (TBAs) were measured and the oral glucose tolerance test (OGTT) was performed after overnight fasting at the eighth weekend. RNA and protein levels of FXR, LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction (RT-PCR).

RESULTSThe insulin resistance rats showed higher glucose, lipid files and lower expression of FXR compared with normal control rats (P > 0.05). The diabetic model rats showed significantly higher glucose, lipid files, TBA and lower expression of FXR compared with insulin resistance rats (P < 0.05). The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats (P < 0.05).

CONCLUSIONSChanges in bile acid homeostasis, including the alterations of bile acid levels and bile acid receptors, are either a cause or a consequence of the metabolic disturbances observed during diabetic models. Statin therapy induced hyperglycemia may be related with FXR, SHP, LXR-α and Srebp-1 pathways.

Animals ; Blood Glucose ; drug effects ; metabolism ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Glucose Tolerance Test ; Homeostasis ; drug effects ; Insulin Resistance ; physiology ; Liver X Receptors ; Male ; Orphan Nuclear Receptors ; metabolism ; Rats ; Rats, Wistar ; Receptors, Cytoplasmic and Nuclear ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Simvastatin ; therapeutic use ; Sterol Regulatory Element Binding Protein 1 ; metabolism

OBJECTIVETo investigate whether RNA interference (RNAi) of LXRα gene in donor rats with fatty liver improves liver graft function after transplantation.

METHODSFifty donor SD rats were fed a high-fat diet and 56% alcohol to induce macrovesicular steatosis exceeding 60% in the liver. The donor rats were injected via the portal veins with 7 × 10⁷ TU LXRα-RNAi-LV mixture (n=25) or negative control-LV (NC-LV) vector (n=25) 72 h before orthotopic liver transplantation. At 2, 24, and 72 h after the transplantation, the recipient rats were sacrificed to examine liver transaminases, liver graft histology, immunostaining (TUNEL), and protein and mRNA levels of LXRα.

RESULTSLentivirus-LXRα RNAi inhibited LXRα gene expression at both the mRNA and protein levels in the liver graft and reduced the expressions of SREBP-1c and CD36 as compared with the controls, resulting also in reduced fatty acid accumulation in the hepatocytes. The recipient rats receiving RNAi-treated grafts showed more obvious reduction in serum ALT, AST, IL-1β and TNF-α levels, and exhibited milder hepatic pathologies than the control rats after the transplantation. TUNEL assay demonstrated a significant reduction in cell apoptosis in LXRα-RNAi-LV-treated liver grafts, and the rats receiving treated liver grafts had a prolonged mean overall survival time.

CONCLUSIONLXRα-RNAi-LV treatment of the donor rats with fatty liver can significantly down-regulate LXRα gene expression in the liver graft and improve the graft function and recipient rat survival after liver transplantation.

Animals ; Fatty Liver ; genetics ; surgery ; Gene Expression Regulation ; Hepatocytes ; cytology ; Lentivirus ; Liver ; physiology ; Liver Transplantation ; Liver X Receptors ; Orphan Nuclear Receptors ; genetics ; RNA Interference ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley

Nuclear receptor transcription factors are ligand-activated proteins that control various biological events from cell growth and development to lipid metabolism, and energy and glucose homeostasis. Nuclear receptors are important drug targets for metabolic diseases. Liver X receptors (LXRs) are nuclear receptor transcription factors that play essential roles in regulation of cholesterol, triglyceride, fatty acid, and glucose homeostasis. LXR-deficient mice have shown the association of LXR-signaling pathway dysfunction with several human pathologies including atherosclerosis, hyperlipidemia, Alzheimer's disease and cancer. Thus, LXRs are promising pharmacological targets for these diseases. Synthetic LXR agonists may lower cholesterol, but increase triglyceride and induce fatty liver. The naturally occurring LXR ligands, with moderate activity, may serve as nutraceuticals for prevention or treatment of the disorders, while minimizing potential side effects. In this review, recent advances in natural LXR modulators are summarized including agonist, antagonist and the modulator of LXR pathway.
Animals ; Biological Products ; pharmacology ; Humans ; Liver ; metabolism ; physiopathology ; Liver X Receptors ; Orphan Nuclear Receptors ; drug effects ; physiology

Adolescent ; Child ; Child, Preschool ; DNA Mutational Analysis ; Diagnosis, Differential ; Humans ; Infant ; Infant, Newborn ; Liver Diseases ; diagnosis ; genetics ; pathology ; Lung Diseases ; diagnosis ; genetics ; pathology ; Magnetic Resonance Imaging ; Mutation ; Polycystic Kidney, Autosomal Dominant ; diagnosis ; genetics ; pathology ; Polycystic Kidney, Autosomal Recessive ; diagnosis ; genetics ; pathology ; Prenatal Diagnosis ; Receptors, Cell Surface ; genetics ; Tomography, X-Ray Computed

BACKGROUNDABCA7 is a member of the ABCA subfamily that shows a high degree of homology to ABCA1 and, like ABCA1, mediates cellular cholesterol and phospholipid release by apolipoproteins when transfected in vitro. However, expression of ABCA7 has been shown to be downregulated by increased cellular cholesterol while ABCA1 was upregulated.

METHODSThe underlying mechanism for this effect was examined in ABCA1 or ABCA7-transfected HEC293. Lipid content in the medium and cells was determined by enzymatic assays. Gene expression was quantitated by real time PCR, and protein content was determined by Western blotting.

RESULTSWhile ABCA7 mRNA was decreased by 25-hydroxycholesterol treatment, ABCA1 was apparently increased. Treatment with the synthetic LXR agonist T0901317 (T09) upregulated ABCA1 expression and apoAI-mediated cellular lipid release in ABCA1-transfected HEC293 cells, but ABCA7 expression and cellular lipid release in ABCA7-transfected HEC293 cells showed no obvious changes.

CONCLUSIONThe ABCA7 gene is regulated by sterol in a direction opposite to that of ABCA1.

ATP Binding Cassette Transporter 1 ; analysis ; genetics ; physiology ; ATP-Binding Cassette Transporters ; analysis ; genetics ; physiology ; Amino Acid Sequence ; Apolipoprotein A-I ; physiology ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Hydrocarbons, Fluorinated ; pharmacology ; Hydroxycholesterols ; pharmacology ; Lipid Metabolism ; Liver X Receptors ; Molecular Sequence Data ; Orphan Nuclear Receptors ; agonists ; Sulfonamides ; pharmacology

AIM: Silybin (SB), a major constituent of the milk thistle, has been used to treat several liver disorders. However, liver diseases were always accompanied by CYP450 dysfunction. This study was designed to explore the relationship between the hepatoprotective effect and CYP3A regulation of SB during thioacetamide (TAA)-induced rat liver injury. METHODS: Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotectinve effect of SB. α-SMA were detected by immunohistochemical analysis and cytokine release in rat liver was determined by ELISA assay. CYP3A and PXR expression were determined by RT-PCR and Western blot analysis, and CYP3A activity was based on the midazolam 4-hydroxylation reaction. Also, siRNA transfection was induced in HepG2 cells to evaluate the effect of PXR on cytotoxicity and CYP3A4 dysregulation caused by TAA. RESULTS: SB showed powerful hepatoprotective effects, and anti-inflammatory and anti-fibrosis effects, and reversed the loss of CYP3A and PXR in TAA-injured rat liver, and decreased PXR translocation into the cell nucleus. PXR silencing weakened the effect of SB on cytoprotection and CYP3A regulation. CONCLUSIONS PXR was a very important factor of CYP3A regulation and might be the target of SB in TAA-induced liver disease. Also, because of the potential interactions of SB and co-administered medicines, it might be necessary to adjust the dosage in the clinical medication of liver disease.
Animals ; Chemical and Drug Induced Liver Injury ; drug therapy ; enzymology ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Liver ; drug effects ; enzymology ; metabolism ; Male ; Milk Thistle ; chemistry ; Pregnane X Receptor ; Rats ; Rats, Sprague-Dawley ; Receptors, Steroid ; genetics ; metabolism ; Signal Transduction ; drug effects ; Silybin ; Silymarin ; administration & dosage ; Thioacetamide ; adverse effects