Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36.
Animals ; Anticholesteremic Agents/*pharmacology ; Antigens, CD36/antagonists & inhibitors/genetics/*metabolism ; Cells, Cultured ; Ezetimibe/*pharmacology ; Flow Cytometry ; Glucose/toxicity ; Insulin/genetics/metabolism/secretion ; Insulin-Secreting Cells/cytology/*drug effects/metabolism ; Male ; Palmitic Acid/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction

OBJECTIVETo determine the effects of probucol on serum parameters and liver histopathology in rats with non-alcoholic steatohepatitis (NASH) and explore the mechanisms.

METHODSForty male Sprague-Dawley rats were randomly assigned into 4 equal groups, namely the normal control group (NC group) with a standard feeding, high-fat diet group (HD group) fed with a high-fat diet, probucol (500 mg/kg daily) control group (NP group) fed with standard diet, and probucol group fed with a high-fat diet (HP group). After 15 weeks of feeding, the rats were euthanized for histopathological inspection of the liver with HE staining and detection of farnesoid X receptor (FXR), SHP and SREBP-1C expressions using semi-quantitative RT-PCR and Western blotting.

RESULTSAfter the 15-week feeding, the rats in HP group had significantly lower levels of serum ALT, AST, cholesterol, bile acid, and free fatty acid than those in HD group (P<0.01 or 0.05). Compared with the normal control group, high-fat diet feeding resulted in significantly decreased mRNA and protein levels of FXR and SHP (P<0.05) and significantly increased SREBP-1C level (P<0.05). These high-fat diet-induced gene expression changes were reversed by probucol intervention (P<0.05).

CONCLUSIONProbucol treatment has beneficial effects on serum parameters, hepatic steatosis, and lobular inflammation in high-fat diet-induced NASH possibly by up-regulating FXR expression.

Animals ; Anticholesteremic Agents ; pharmacology ; Diet, High-Fat ; Disease Models, Animal ; Male ; Non-alcoholic Fatty Liver Disease ; blood ; drug therapy ; Probucol ; pharmacology ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley

AIM: The current study was undertaken to assess anti-hyperlipidemic activity of Pistacia lentiscus fatty oil (PLFO) in rabbits following a hyperlipidemic diet. METHOD: Twenty healthy female (WNZ) rabbits were divided into four groups of five animals each: (a) normal control (NC group) receiving standard diet, (b) hyperlipidemic control (EY) group receiving standard diet and gavaged daily with egg yolk (10 mL), (c) hyperlipidemic + PLFO (EY + PLFO) group receiving as the EY group and treated daily with PLFO (2 mL/kg BW, (d) hyperlipidemic + simvastatin (EY + SVS) group receiving as the EY group and treated once daily with 2.5 mg/kg BW of simvastatin. At the end of the six-week experimental period, the lipidemic profiles of the different groups were investigated. RESULTS: In the EY group, the egg yolk resulted in a significant increase of total cholesterol (TC), triglycerides (TG), HDL-C, LDL-C, and the LDL-C/HDL-C ratio. Both the EY + PLFO and EY + SVS groups, when compared to the EY group, showed a significant decrease of TC, TG, LDL-C, and the LDL-C/HDL-C ratio. However, with respect to HDL-C the differences were not significant. The TGs were significantly lower (P < 0.001) in the simvastatin-treated group when compared to rabbits treated in the PLFO group. CONCLUSION The study concludes that P. lentiscus fatty oil (PLFO) possesses anti-hyperlipidemic properties at least in reducing total cholesterol, LDL-cholesterol and triglycerides.
Animals ; Anticholesteremic Agents ; pharmacology ; therapeutic use ; Cholesterol ; blood ; Cholesterol, HDL ; blood ; Cholesterol, LDL ; blood ; Diet ; Egg Yolk ; Female ; Fruit ; Hyperlipidemias ; blood ; drug therapy ; etiology ; Lipids ; blood ; Phytotherapy ; Pistacia ; Plant Oils ; pharmacology ; therapeutic use ; Rabbits ; Simvastatin ; pharmacology ; therapeutic use ; Triglycerides ; blood

ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I (apoA-I), and plays a key role in the initial steps of the whole process of reverse cholesterol transport (RCT). Upregulation of ABCA1 is beneficial for atherosclerosis (AS) prevention and/or therapy, which indicated that ABCA1 was a target for anti-AS drug development. In the previous study, a high-throughput screening method was established using ABCA1p-LUC HepG2 cell line to find the upregulators of ABCA1. In the present study, compound 2030421B was found using this method, with EC50 of 0.50 microg x mL(-1). The compound was further identified as an upregulator of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analysis. Studies also showed that the 2030421B could induce apoA-I-mediated cholesterol efflux and inhibit lipids uptake into mouse peritoneal macrophages RAW264.7.
ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Animals ; Anticholesteremic Agents ; administration & dosage ; chemistry ; pharmacology ; Apolipoprotein A-I ; metabolism ; Benzaldehydes ; administration & dosage ; chemistry ; pharmacology ; Biological Transport ; Cells, Cultured ; Cholesterol ; secretion ; Dose-Response Relationship, Drug ; Hep G2 Cells ; High-Throughput Screening Assays ; Humans ; Lipid Metabolism ; Lipids ; analysis ; Macrophages, Peritoneal ; cytology ; metabolism ; Mice ; Molecular Structure ; RNA, Messenger ; Up-Regulation ; drug effects

This study is to observe anti-lipotoxic effect of sesamin on renovascular hypertensive rats fed with a high-fat, high-sucrose diet. Thirty-four complex model rats were induced by two-kidney, one-clip method and on high-fat and refined-carbohydrate diet for thirteen weeks. From the fifth week, intragastric administration of sesamin (120, 60 and 30 mg x kg(-1) x d(-1)) lasted for eight weeks. Blood pressure (BP), blood fat (BF), blood glucose (BG), free fatty acids (FFA), insulin (Ins), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined. Pathological changes of pancreas, perirenal fat and liver were semiquantitatively analyzed. In sesamin (120 and 60 mg x kg(-1) x d(-1)) group, it was found that there were decrease of levels of BP, BF, BG, TNF-alpha, IL-6 and FFA, improvement of insulin resistance and glucose tolerance, alleviation of body weight, humid weight of fat, liver and pancreas and their organ index, and reduction of islet cell hyperplasia and amount of lipid droplet vacuoles in lipocyte and hepatocyte. It is implied that sesamin had anti-lipotoxic effect and its mechanism may be closely associated with the amelioration of insulin resistance via reducing lipidoses in hepatocyte and inflammatory adipokines such as TNF-alpha and IL-6.
Adipocytes ; drug effects ; Animals ; Anticholesteremic Agents ; administration & dosage ; pharmacology ; Antihypertensive Agents ; administration & dosage ; pharmacology ; Blood Glucose ; metabolism ; Blood Pressure ; drug effects ; Body Weight ; drug effects ; Cholesterol ; blood ; Diet, High-Fat ; Dioxoles ; administration & dosage ; pharmacology ; Dose-Response Relationship, Drug ; Fatty Acids, Nonesterified ; blood ; Glucose Tolerance Test ; Hypertension, Renovascular ; blood ; pathology ; Insulin ; blood ; Insulin Resistance ; Interleukin-6 ; blood ; Islets of Langerhans ; pathology ; Lignans ; administration & dosage ; pharmacology ; Liver ; pathology ; Male ; Pancreas ; pathology ; Rats ; Rats, Sprague-Dawley ; Sucrose ; Triglycerides ; blood ; Tumor Necrosis Factor-alpha ; blood

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced.
Animals ; Anticholesteremic Agents ; chemical synthesis ; chemistry ; pharmacology ; Azepines ; chemical synthesis ; chemistry ; pharmacology ; Benzene Derivatives ; chemical synthesis ; chemistry ; pharmacology ; Chenodeoxycholic Acid ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Crystallization ; Humans ; Indoles ; chemical synthesis ; chemistry ; pharmacology ; Isoxazoles ; chemical synthesis ; chemistry ; pharmacology ; Ligands ; Molecular Structure ; Multienzyme Complexes ; chemical synthesis ; chemistry ; pharmacology ; Pregnenediones ; chemical synthesis ; chemistry ; pharmacology ; Receptors, Cytoplasmic and Nuclear ; agonists ; antagonists & inhibitors ; metabolism ; Structure-Activity Relationship

Osteoclasts, together with osteoblasts, control the amount of bone tissue and regulate bone remodeling. Osteoclast differentiation is an important factor related to the pathogenesis of bone-loss related diseases. Reactive oxygen species (ROS) acts as a signal mediator in osteoclast differentiation. Simvastatin, which inhibits 3-hydroxy-3-methylglutaryl coenzyme A, is a hypolipidemic drug which is known to affect bone metabolism and suppresses osteoclastogenesis induced by receptor activator of nuclear factor-kappaB ligand (RANKL). In this study, we analyzed whether simvastatin can inhibit RANKL-induced osteoclastogenesis through suppression of the subsequently formed ROS and investigated whether simvastatin can inhibit H2O2-induced signaling pathways in osteoclast differentiation. We found that simvastatin decreased expression of tartrate-resistant acid phosphatase (TRAP), a genetic marker of osteoclast differentiation, and inhibited intracellular ROS generation in RAW 264.7 cell lines. ROS generation activated NF-kappaB, protein kinases B (AKT), mitogen-activated protein kinases signaling pathways such as c-JUN N-terminal kinases, p38 MAP kinases as well as extracellular signal-regulated kinase. Simvastatin was found to suppress these H2O2-induced signaling pathways in osteoclastogenesis. Together, these results indicate that simvastatin acts as an osteoclastogenesis inhibitor through suppression of ROS-mediated signaling pathways. This indicates that simvastatin has potential usefulness for osteoporosis and pathological bone resorption.
Acid Phosphatase/genetics/metabolism ; Animals ; Anticholesteremic Agents/*pharmacology ; Blotting, Western ; *Cell Differentiation ; Cells, Cultured ; Hydrogen Peroxide/pharmacology ; Isoenzymes/genetics/metabolism ; Macrophages/cytology/drug effects/metabolism ; Mice ; Mitogen-Activated Protein Kinases/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Osteoclasts/*cytology/*drug effects/metabolism ; RANK Ligand/metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Simvastatin/*pharmacology

OBJECTIVETo evaluate whether taking atorvastatin for long time has positive effects on age-related renal impairment.

METHODS20-month-age normal female Wistar rats were divided into three groups (n = 9). First group were fed atorvastatin 10 mg/(kg x d). Second group were fed atorvastatin 1 mg/(kg x d). Third group were fed the same volume normal saline served as control. All the rats were sacrificed after four months. 3-month-age normal female Wistar rats (n = 9) also served as normal control. Kidney weight, serum creatinine (Scr) and blood-lipoids were measured. Paraffin sections of renal tissues were stained with PAS and Sirius red. Sclerosis index of glomerulus was calculated.

RESULTSRenal mass diminution was found in all the groups of aging rats. Scr was decreased in the group of aging rats with atorvastatin 1 mg/(kg x d). The level of blood-lipoids of aging rats was higher than that of young rats. The level of serum cholesterol and low-density lipoprotein (LDL) were decreased in first group (both P < 0.05) and only LDL decreased in second group (P < 0.05). Morphological changes of aging kidney were focal segmental glomerulosclerosis, widen of mesangial region, infiltration of inflammatory cells and sclerosis of arteriole. The treatment of atorvastatin improved the pathologic changes in the aging rats significantly, especially in the first group.

CONCLUSIONTaking atorvastatin for long time can notably improve the pathological changes of aging kidney. All these effects may be induced by lowing of blood-lipoids, relieving the sclerosis of renal arteriole and reducing the infiltration of inflammatory cells.

Aging ; physiology ; Animals ; Anticholesteremic Agents ; administration & dosage ; pharmacology ; Arteriosclerosis ; pathology ; prevention & control ; Atorvastatin Calcium ; Female ; Heptanoic Acids ; administration & dosage ; pharmacology ; Kidney ; pathology ; Kidney Diseases ; prevention & control ; Pyrroles ; administration & dosage ; pharmacology ; Rats ; Rats, Wistar ; Renal Artery ; pathology

ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Anticholesteremic Agents ; pharmacology ; Cell Line ; Drug Synergism ; Humans ; Macrophages ; cytology ; metabolism ; PPAR gamma ; metabolism ; Pravastatin ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Thiazolidinediones ; pharmacology ; Up-Regulation ; drug effects

BACKGROUNDProbucol is known to reduce the development of atherosclerotic lesions, but its impact on vascular remodeling associated with de novo atherosclerosis is incompletely understood. We therefore examined the effect of probucol on vascular remodeling in a rabbit model of established atherosclerosis.

METHODSAortic atherosclerosis was induced by a combination of endothelial injury and 10 weeks' atherogenic diet. Animals were then randomized to receive the foregoing diet without or with 1% (wt/wt) probucol for 16 weeks. At the end of week 26, in vivo intravascular ultrasound, pathological, immunohistochemical and gene expression studies were performed.

RESULTSProbucol significantly decreased vessel cross-sectional area, plaque area and plaque burden without effect on lumen area. More negative remodeling and less positive remodeling occurred in the abdominal aortas of probucol group than the control group (56% vs. 21%, 18% vs. 54%, respectively, both P < 0.01). In addition, the probucol group showed a smaller mean remodeling index relative to the control group (0.93 ± 0.13 vs. 1.05 ± 0.16, P < 0.01). Furthermore, probucol treatment decreased macrophage infiltration, inhibited apoptosis of cells within plaques, and reduced the production of matrix metalloproteinases-2, -9, cathepsin K and cathepsin S (all P < 0.01).

CONCLUSIONSThese findings suggest that probucol may attenuate the enlargement of atherosclerotic vessel walls and be associated with a negative remodeling pattern without affecting the lumen size. This effect may involve inhibition of extracellular matrix degradation and prevention of apoptosis in atherosclerotic plaques.

Animals ; Anticholesteremic Agents ; pharmacology ; Aorta ; pathology ; Apoptosis ; drug effects ; Atherosclerosis ; drug therapy ; metabolism ; pathology ; Lipids ; blood ; Macrophages ; drug effects ; physiology ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Matrix Metalloproteinase 9 ; metabolism ; Oxidative Stress ; Probucol ; pharmacology ; Rabbits ; Ultrasonography, Interventional ; methods