ABSTRACT
The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by regulating the cellular efflux of cholesterol. Since ABCA1 plays a pivotal role in cholesterol homeostasis and HDL metabolism, identification of a novel substance that is capable of increasing its expression would be beneficial for the prevention and therapy of atherosclerosis. In the present study, we studied the effects of ethanolic extracts of Brazilian red propolis (EERP) on ABCA1 expression and cholesterol efflux in THP-1 macrophages. EERP enhanced PPARγ and liver X receptor (LXR) transcriptional activity at 5-15µg/ml, which was associated with upregulation of PPARγ and LXRα expression. It was also found that EERP increase the activity of the ABCA1 promoter, which is positively regulated by LXR. Consistent with these findings, treatment with EERP increased both mRNA and protein expression of ABCA1. Finally, EERP upregulated ApoA-I-mediated cholesterol efflux. Our results showed that EERP promote ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression via induction of PPARγ/LXR.
Subject(s)
ATP Binding Cassette Transporter 1/genetics , Cholesterol/metabolism , Macrophages/drug effects , Plant Extracts/pharmacology , Propolis/chemistry , ATP Binding Cassette Transporter 1/metabolism , Animals , Apolipoprotein A-I/drug effects , Apolipoprotein A-I/metabolism , Biological Transport/drug effects , Cattle , Cell Line , Cell Survival/drug effects , Humans , Liver X Receptors , Macrophages/metabolism , Models, Biological , Orphan Nuclear Receptors/drug effects , Orphan Nuclear Receptors/genetics , PPAR gamma/drug effects , PPAR gamma/genetics , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, Genetic/drug effectsABSTRACT
OBJECTIVE: It has been suggested that apo A-I can inhibit cholesterol crystal nucleation in vitro, and ursodeoxycholic acid (UDCA) is a safe and effective treatment for selected patients with cholesterol gallstones the aim of this study was to investigate the effect of UDCA on the steady-state levels (SSL) of apo A-I mRNA in the liver, as well as serum apo A-I, in patients with cholesterol gallstones. DESIGN: Twenty Mexican patients with symptomatic radiolucent gallstones were randomized and assigned in a double blind fashion to groups that were administered either UDCA (4 mg/kg per day) or placebo for 10 to 15 days before cholecystectomy. Apo A- I mRNA levels in liver and gallbladder tissues were determined by northern blot and serum levels of apo A- I by turbidimetric method. METHODS: Apo A- I mRNA levels were higher in nine of the 10 patients who received UDCA and in comparison to those to the placebo group. In the gallbladder apo A- I mRNA levels were undetected. Serum levels (mg/dL) of apo A- I were similar in both UDCA and placebo groups after treatment (111.7 +/- 29.8 vs 115.6 +/- 25.4). CONCLUSIONS: The results of this study shown that apo A- I mRNA gene express at the mRNA level in the liver but not in the gallbladder of patients with cholesterol gallstones treated with UDCA.
Subject(s)
Apolipoprotein A-I/genetics , Cholagogues and Choleretics/therapeutic use , Cholelithiasis/drug therapy , Liver/metabolism , RNA, Messenger/drug effects , Ursodeoxycholic Acid/therapeutic use , Adult , Apolipoprotein A-I/drug effects , Apolipoprotein A-I/metabolism , Cholecystectomy , Cholelithiasis/genetics , Cholelithiasis/surgery , Double-Blind Method , Gene Expression , Humans , Middle Aged , RNA, Messenger/genetics , Treatment OutcomeABSTRACT
PURPOSE: To evaluate the effects of pravastatin on lipoproteins, Lp (a), apo B and apo A-I and its tolerability in primary hypercholesterolemic patients in our outpatient lipid clinic. METHODS: Twenty-two primary hypercholesterolemic patients were evaluated. They had all been treated previously with other hypocholesterolemic drugs, including the statins, forming a specific and homogeneous group with hypercholesterolemia and definite coronary risk. After 7 weeks with American Heart Association phase I diet and placebo drug, pravastatin was administered during 12 weeks. All patients received an initial daily dose of 10 mg for six weeks. After this period, this dose was increased to 20 mg. The levels of cholesterol, triglycerides, high-density lipoprotein, lipoprotein (a) and apolipoproteins A-1 and B were determined. RESULTS: No changes occurred with diet and placebo, but pravastatin at a daily dose of 10 mg, reduced significantly cholesterol level (7.22%), LDL-cholesterol (13.08%) and increased HDL-cholesterol (7.81%). The results were better with 20 mg, achieving a reduction of (28.21%) in cholesterol, (36.88%) in LDL-cholesterol, (17.06%) in apo B level and an increase of (10.06%) in HDL-cholesterol. The smaller effect observed with the more commonly used dosage (10 mg/day) was most probably due to the characteristics of the sample with already established hypercholesterolemia, being thus dependent of higher concentrations of medications, as observed in previous treatments in our outpatient clinic. Side affects with this drug were rare. No biochemical changes were observed that would interrupt the continuation of therapy. CONCLUSION: Pravastatin was well tolerated and promoted favorable changes in the total cholesterol, LDL, apo B and cholesterol/HDL and LDL/HDL ratios of primary hypercholesterolemic patients.