BACKGROUND: The etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities. METHODS: We measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively. RESULTS: We found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (-16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA. CONCLUSIONS: We demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition.
- MeSH
- adenosintrifosfát MeSH
- aneurysma břišní aorty * MeSH
- antiflogistika MeSH
- ateroskleróza * MeSH
- cholesterol metabolismus MeSH
- cholesterolacyltransferasa metabolismus MeSH
- HDL-cholesterol MeSH
- homeostáza MeSH
- lecitiny MeSH
- lidé MeSH
- lipoproteiny metabolismus MeSH
- metaloproteasy metabolismus MeSH
- transportní proteiny pro estery cholesterolu MeSH
- zánět metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo‐controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.
- MeSH
- cholesterol MeSH
- cholesterolacyltransferasa terapeutické užití MeSH
- infarkt myokardu přední stěny * MeSH
- infarkt myokardu s elevacemi ST úseků * diagnostické zobrazování farmakoterapie MeSH
- lecitincholesterolacyltransferasa * terapeutické užití MeSH
- lecitiny terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipoproteiny HDL terapeutické užití MeSH
- statiny * terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- randomizované kontrolované studie MeSH
High levels of fructose induce hypertriglyceridemia, characterized by excessive levels of triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL); however, the underlying mechanisms are poorly understood. The aim of this short communication was to examine hepatic changes in the expression of genes related to cholesterol metabolism in rats with hypertriglyceridemia induced by high-fructose or high-glucose diets. Rats were fed a 65 % (w/w) glucose diet or a 65 % (w/w) fructose diet for 12 days. Serum levels of triglycerides, total cholesterol, and VLDL+LDL-cholesterol, hepatic levels of triglycerides and cholesterol, and ACAT2 expression at the gene and protein levels were significantly higher in the fructose diet group compared to the glucose diet group. The hepatic levels of Abcg5/8 were lower in the fructose group than in the glucose group. Serum high-density lipoprotein (HDL)-cholesterol and hepatic expression levels of Hmgcr, Ldlr, Acat1, Mttp, Apob, and Cyp7a1 did not differ significantly between groups. These findings suggest that high-fructose diet-induced hypertriglyceridemia is associated with increased hepatic ACAT2 expression.
- MeSH
- cholesterolacyltransferasa biosyntéza genetika MeSH
- exprese genu MeSH
- fruktosa aplikace a dávkování škodlivé účinky MeSH
- hypertriglyceridemie chemicky indukované genetika metabolismus MeSH
- játra účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- beauverolidy, beauveriolidy,
- MeSH
- Alzheimerova nemoc farmakoterapie patofyziologie MeSH
- amyloidní beta-protein MeSH
- ateroskleróza farmakoterapie patofyziologie MeSH
- Beauveria metabolismus MeSH
- cholesterolacyltransferasa antagonisté a inhibitory fyziologie MeSH
- cyklické peptidy terapeutické užití MeSH
- depsipeptidy * terapeutické užití MeSH
- fungální proteiny * biosyntéza MeSH
- kalmodulin antagonisté a inhibitory fyziologie MeSH
- lidé MeSH
- makrofágy patologie účinky léků MeSH
- myši MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- Publikační typ
- práce podpořená grantem MeSH
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
- MeSH
- anticholesteremika terapeutické užití MeSH
- apolipoprotein A-I terapeutické užití MeSH
- arterioskleróza epidemiologie patofyziologie MeSH
- cholesterol fyziologie krev MeSH
- cholesterolacyltransferasa fyziologie MeSH
- lidé MeSH
- lipoproteiny HDL metabolismus účinky léků MeSH
- membránové transportní proteiny fyziologie MeSH
- proteiny přenášející fosfolipidy MeSH
- Check Tag
- lidé 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
