Lipid-lowering Drugs On The B Family Of Type I Scavenger Receptor Expression And Function

BackgroudAbout 70% of the diabetics died of cardiovascular diseases. Diabetic dyslipidemia (high triglyceride, low high-density lipoprotein cholesterol and moderatly elevated small dense low-density lipoprotein cholesterol) is hotspot issue currently. Studies indicate that reducing LDL-C levels and/or increasing HDL-C levels can decrease efficiently the incidence of CVD which provided strong evidence to support aggressive treatment for diabetic dyslipidemia.As the most important anti-atherosclerotic mechanism in vivo, reverse cholesterol transport (RCT) is a process which dynamically transport of excess cholesterol from the periphery into the liver, followed by excretion in the feces. Firstly the cholesterol and phospholipids efflux from peripheral tissue and cells to pre-PHDL or lipid-poor apoA-I mostly mediated byATP-binding cassette transporter A1 ,G1(ABCA1,ABCG1) and SR-BI. Secondly the lipids exchange between HDL and LDL/VLDL with the presecnce of cholesteryl ester transfer protein (CETP). Finally the hepatocytes selective uptake HDL-C via SR-BI or endocytose LDL via LDLR, and excrete.Scavenger receptor class B type I (SR-BI) had already proved in molecular level as the sole HDL receptor which locates on celluar membrane. SR-BI has various ligands, and it plays an important role in the bidirectional cholesterol exchange between cells and HDL particles. As the HDL specific receptor, SR-BI plays an important role in the HDL metabolism and the process of RCT. But under the pathological diabetic dyslipidemia and with the presence of lipid-lowering drug, the changes of SR-BI expression and function are still unknown.ObjectivesThe aim of this study is using diabetic dyslipidemia animal model to investigate the changes of the liver SR-BI expression in diabetes on the impact of lipid-lowering drugs; To observe SR-BI expression and the ability of selective uptake HDL-C on HepG2 cells with the presence of lipid-lowering drugs, so provide the evidence and elucidate the function of SR-BI in HDL metabolism, the RCT process and atherosclerosis.Methods1. Establish the diabetic dyslipidemia hamster model induced by high glucose and fat diets and STZ intraperitoneal injection.2. Separately Quantify SR-BI expression at both mRNA and protein levels on hepatocytes in diabetic hamster group as well as in control group by RT-PCR and Western Blot, with and without the treatment of fluvastatin of different dosages and different incubation time.3. Separately Quantify SR-BI expression on HepG2 cells at both mRNA and protein levels by RT-PCR and Western Blot under the treatments of different lipid-lowering drugs (fluvastatin, fenofibrate, and atorvastatin) before and after the incubation with PPAR-αinhibitor MK886 respectively..4. Observe the ability of selective uptake of exogenous fluresent and radioactive double-labeled HDL by HepG2 cells were quantified before and after fluvastatin intervention of different dosages and incubation time.Result1. Animal models developed higher fasting glucose levels, dyslipidemia, and insulin sensitivity index decreased.2. SR-BI mRNA and protein expression on hepatocytes in diabetic dyslipidemia animals were higher than that of control animals(p<0.05). Fluvastatin could dose-and time-dependently increase SR-BI mRNA and protein expression in diabetic dyslipidemia animals.3. Fluvastatin or atovastatin could dose- and time-dependently increase HepG2 cells' SR-BI mRNA and protein expression(p<0.05). , which could not be blocker by PPAR-αpathway inhibitor MK886. There was no significant difference between two statins. Conversly fenofibrate could dose- and time-dependently inhibit SR-BI mRNA and protein expression(p<0.05) on HepG2 cells, which could be totally blocked by MK886. 4. Fluvastatin could dose- and time-dependently promoted selective uptake of HDL-C by SR-BI in HepG2 cells (p<0.05).Conclusions1. In diabetic dyslipidemia hamster, SR-BI mRNA and protein expression on hepatocytes increased significantly.2. Fluvastatin dose- and time-dependently increased SR-BI mRNA and protein expression on diabetic hamster liver cells as well as on HepG2 cells, and moreover promoted the selective uptake of HDL-C by SR-BI in HepG2 cells.3. Atovastatin could dose- and time-dependently increased SR-BI mRNA and protein expression on HepG2 cells, which was independent of PPAR-αpathway.4. Fenofibrate could dose- and time-dependently reduce SR-BI mRNA and protein expression on HepG2 cells through the pathway of PPAR-α.