INTRODUCTION: The aim of study was to evaluate impact of long-term dietary cholesterol overload on the cholesterol homeostasis and liver regeneration. MATERIAL AND METHODS: Serum lipid parameters, 14C-cholesterol incorporation, liver DNA synthesis and protein expression was determined in partially hepatectomized (PH) rats fed with a standard (SLD) or hypercholesterolemic (CHOL) diet. RESULTS: 29-day intake of CHOL diet before PH produced increase in serum total cholesterol, LDL lipoprotein, and triglyceride concentration. PH provoked decrease in serum total cholesterol and triglyceride concentration in both groups. PH was associated with increase in serum ALT activity more pronounced in CHOL animals. Hepatic DNA synthesis was increased after PH in both groups, but lower in CHOL. Hypercholesterolemic diet reduced the absorption of radiolabelled cholesterol in intestine and then activity in blood and liver. The 14C-cholesterol hepatic activities tend to increase after PH in both groups. CHOL diet produced up-regulation of Acyl-CoA:cholesterol acyltransferase-2 protein expression. PH was associated with increase of LDL receptor and Acyl-CoA:cholesterol acyltransferase-2 protein expression in both dietary groups. DISCUSSION: Liver regeneration after PH is negatively influenced by CHOL diet. The increased uptake of cholesterol in the liver after PH associated with up-regulation of LDL receptor protein expression suggests preferential use of extrahepatic cholesterol by the liver.

• MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterolacyltransferasa účinky léků   metabolismus   MeSH
• DNA účinky léků   metabolismus   MeSH
• hepatektomie MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• krysa rodu rattus MeSH
• lipoproteiny LDL účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• radioizotopy uhlíku MeSH
• regenerace jater účinky léků   MeSH
• triglyceridy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin. DESIGN: Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection. RESULTS: Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD. CONCLUSION: The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans.

• MeSH
• aromatické hydroxylasy antagonisté a inhibitory   metabolismus   MeSH
• cholesterol dietní farmakologie   MeSH
• fluorbenzeny farmakologie   MeSH
• genetická transkripce účinky léků   MeSH
• hyperlipoproteinemie typ IV farmakoterapie   genetika   metabolismus   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mutantní kmeny potkanů MeSH
• potkani Wistar MeSH
• pyrimidiny farmakologie   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• statiny farmakologie   MeSH
• steroid-21-hydroxylasa antagonisté a inhibitory   genetika   metabolismus   MeSH
• sulfonamidy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The aim of the study was to evaluate whether cholesterol-rich diet affects transforming growth factor-β-RIII (endoglin) levels in blood and 2 endoglin-related pathways in the aorta of ApoE/LDLR double knockout mice. METHODS AND RESULTS: Mice were fed either chow diet (CHOW) (n=8) or by 1% cholesterol-rich diet (CHOL) (n=8). Biochemical analysis of cholesterol and endoglin levels in blood, lesion size area, immunohistochemistry and Western blot analysis in mice aortas were performed. Biochemical analysis showed that cholesterol-rich diet resulted in a significant increase of cholesterol and endoglin levels in serum, and increased plaque size in the aorta. In addition, a cholesterol-rich diet significantly decreased the expressions of endoglin by 92%, activin receptor-like kinase (ALK)-1 by 71%, p-Smad2 by 21%, and vascular endothelial growth factor (VEGF) by 37% when compared to CHOW mice, but ALK-5, p-Smad1, and endothelial nitric oxide synthase were not significantly affected. CONCLUSIONS: Hypercholesterolemia increases endoglin levels in blood and simultaneously decreases its expression in aorta, together with atherosclerosis protective markers p-Smad2 and VEGF, followed by increased plaque size. Inhibition of endoglin signaling might be one of the mechanisms responsible for the promoting of endothelial dysfunction and atherogenesis. Moreover, the monitoring of endoglin serum levels might represent an attractive blood marker of progression of disease; however, the precise source and role of endoglin in blood serum remains to be elucidated.

• MeSH
• aktivinové receptory typu I metabolismus   MeSH
• aktivinové receptory metabolismus   MeSH
• aorta metabolismus   patologie   MeSH
• apolipoproteiny E nedostatek   genetika   metabolismus   MeSH
• aterosklerotický plát metabolismus   patologie   MeSH
• ateroskleróza metabolismus   patologie   MeSH
• biologické markery krev   MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterol krev   MeSH
• intracelulární signální peptidy a proteiny krev   MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• protein Smad1 metabolismus   MeSH
• protein Smad2 metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• receptory LDL nedostatek   genetika   metabolismus   MeSH
• receptory transformujícího růstového faktoru beta metabolismus   MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Endoglin (a type III TGF-β receptor) is able to modulate ligand binding and signaling by association with the TGF-β type I receptors (ALK-1 and ALK-5). In this study, we hypothesized whether atorvastatin treatment affects endoglin/ALK-1/p-Smad1/VEGF expression in the aorta and endoglin levels in serum in ApoE/LDLR double knockout mice. ApoE/LDLR double knockout mice were fed with a diet containing either 1% of cholesterol (CHOL) or cholesterol with atorvastatin (ATV) at a dose of 50mg/kg/day. Biochemical analysis of cholesterol levels and ELISA analysis of endoglin levels in serum, lesion area size, immunohistochemistry and Western blot analysis in mice aorta were performed. Atorvastatin treatment resulted in a significant decrease of total, VLDL and LDL cholesterol, atherosclerotic lesion size and endoglin serum levels in comparison with CHOL mice. On the other hand, atorvastatin treatment significantly increased the expressions of endoglin by 1431%, ALK-1 by 310%, p-Smad1 by 135% and VEGF by 62% in aorta when compared to CHOL mice. In conclusion, it has been demonstrated that atorvastatin increases endoglin/ALK-1/p-Smad1/VEGF expression in aorta and decreases the size of atherosclerotic lesions, suggesting that activation of this endothelial-protective pathway might support the antiatherogenic effects of atorvastatin. Moreover, atorvastatin concurrently decreased serum levels of endoglin suggesting that monitoring of endoglin levels in blood might represent an important marker of the progression and/or treatment of atherosclerosis.

• MeSH
• aktivinové receptory typu I metabolismus   MeSH
• apolipoproteiny E genetika   MeSH
• aterosklerotický plát chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• ateroskleróza krev   chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• biomarkery farmakologické krev   metabolismus   MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterol krev   MeSH
• fosforylace účinky léků   MeSH
• HDL-cholesterol krev   MeSH
• intracelulární signální peptidy a proteiny krev   metabolismus   MeSH
• krev účinky léků   MeSH
• kyseliny heptylové farmakologie   terapeutické užití   MeSH
• LDL-cholesterol krev   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• protein Smad1 metabolismus   MeSH
• pyrroly farmakologie   terapeutické užití   MeSH
• receptory LDL genetika   MeSH
• Valsalvův sinus metabolismus   patologie   MeSH
• vaskulární endoteliální růstový faktor A metabolismus   MeSH
• VLDL-cholesterol krev   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: There is evidence to suppose that cholesterol-lowering medicine might confer protection against dementia, probably via modulation of cholesterol synthesis in the brain. The aim of the present study was to investigate the potential influence of statins and cholesterol diet on selected parameters relevant to Alzheimer's disease pathophysiology. METHODS: For 15 days, rats were orally administered simvastatin (10 or 20mg/kg b.wt.), atorvastatin (10 or 20mg/kg b.wt.), or aqua (control group); and one group was fed high-cholesterol (2%) diet. At the end of experiments brain (and plasma) cholesterol, lathosterol, hydroxymethylglutaryl-coenzyme A reductase protein, acetylcholinesterase activity, amyloid beta (40 and 42) and cholesterol synthesis rate (using the incorporation of deuterium from deuterated water) were determined and statistically compared to those of aqua. RESULTS: Both statins were able to lower cholesterol in the plasma, but none elicited an effect on total brain cholesterol. Significant reductions of brain lathosterol and cholesterol synthesis rate were observed after simvastatin and atorvastatin treatment. Acetylcholinesterase activity, amyloid beta and hydroxymethylglutaryl-coenzyme A reductase levels remained unaffected by the two drugs. CONCLUSIONS: This study brings additional evidence of a role for statins in cholesterol synthesis in the brain. Our data question the relationship between amyloid beta, acetylcholinesterase activity and cholesterol synthesis in the rat brain as well as the assumption about no exchange between peripheral and brain cholesterol pools.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein biosyntéza   MeSH
• anticholesteremika farmakologie   MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterol biosyntéza   MeSH
• dieta MeSH
• financování organizované MeSH
• hydroxymethylglutaryl-CoA-reduktasy metabolismus   MeSH
• krysa rodu rattus MeSH
• kyseliny heptylové farmakologie   MeSH
• lidé MeSH
• mozek - chemie účinky léků   MeSH
• mozek metabolismus   MeSH
• potkani Wistar MeSH
• pyrroly farmakologie   MeSH
• simvastatin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH

The use of inhibitors of enzyme acyl-CoA: cholesterol acyltransferase (ACAT) seems to be a novel potential approach for a therapeutic treatment of dyslipidaemias and atherosclerosis. VULM 1457 is an ACAT inhibitor, which has expressed potent hypolipidemic and antiatherosclerotic effects in previous studies. In this study, we used streptozocin-induced diabetic rats, which were fed a fat-cholesterol diet to evaluate the affect of VULM 1457 on the atherogenic lipids levels in both plasma and liver. VULM 1457, with a slight influence on triglyceride levels, significantly reduced plasma and hepatic cholesterol concentrations (p < 0.05, p < 0.001; respectively) in the diabetic-hypercholesterolaemic rats.

• MeSH
• cholesterol dietní farmakologie   MeSH
• cholesterol krev   metabolismus   MeSH
• cholesterolacyltransferasa antagonisté a inhibitory   MeSH
• dietní tuky farmakologie   MeSH
• experimentální diabetes mellitus farmakoterapie   krev   MeSH
• hypercholesterolemie farmakoterapie   krev   MeSH
• hypolipidemika MeSH
• inhibitory enzymů farmakologie   MeSH
• játra metabolismus   účinky léků   MeSH
• klofibrát analogy a deriváty   farmakologie   MeSH
• krevní glukóza metabolismus   MeSH
• potkani Wistar MeSH
• triglyceridy krev   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

• MeSH
• aorta chemie   účinky léků   MeSH
• ateroskleróza farmakoterapie   metabolismus   MeSH
• cholesterol dietní farmakologie   MeSH
• diltiazem farmakologie   MeSH
• hořčík analýza   MeSH
• králíci MeSH
• vápník analýza   antagonisté a inhibitory   MeSH
• verapamil farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH