Torcetrapib differentially modulates the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway.

نویسندگان

  • Giovanna Catalano
  • Zélie Julia
  • Eric Frisdal
  • Benoit Vedie
  • Natalie Fournier
  • Wilfried Le Goff
  • M John Chapman
  • Maryse Guerin
چکیده

OBJECTIVE Therapeutic strategies to raise low plasma HDL-cholesterol levels, with concomitant normalization of the intravascular metabolism, physicochemical properties, and antiatherogenic function of HDL particles, are a major focus in atherosclerosis prevention. METHODS AND RESULTS Patients displaying Type IIB hyperlipidemia (n=14) and healthy controls (n=11) were recruited. After drug washout, dyslipidemic patients first received atorvastatin (10 mg/d) for 6 weeks and subsequently torcetrapib/atorvastatin (60/10 mg/d) for the same period. Partial CETP inhibition markedly reduced supranormal CE transfer rates to normal levels from HDL3 (-58%; P<0.0001) to apoB-lipoproteins; endogenous CE transfer rates from HDL2 to apoB-lipoproteins were markedly subnormal as compared to those in control subjects (10.7+/-0.9 versus 29.3+/-4.8 microg CE/h/mL plasma, respectively). Torcetrapib enhanced the subnormal capacity of HDL2 particles from dyslipidemic patients to mediate free cholesterol efflux via both SR-BI and ABCG1 pathways (+38%; P<0.003 and +35%; P<0.03, respectively) as compared to baseline. In vitro observations and in vivo studies in mice demonstrated that CETP inhibition was associated with an enhanced selective hepatic uptake of CE from HDL particles (1.7-fold; P<0.0003). CONCLUSIONS CETP inhibition partially corrected the abnormal physicochemical and functional properties of HDL2 and HDL3 particles in type IIB hyperlipidemia. Enhanced hepatic selective uptake of HDL-CE may compensate for attenuated indirect CE transfer to apoB-containing lipoproteins via CETP attributable to torcetrapib.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia.

OBJECTIVE Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. METHODS AND RESULTS We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol ef...

متن کامل

جدا سازی HDL2 و HDL3 و مقایسه غلظت کلسترول آنها بین گروه شاهد و مبتلایان به آترواسکلروز

The major Lipoprotein classes are heterogenous. Human serum High-Density-Lipoproteins (HDL) are separated into two major subfractions (HDL2, d=1.063-1.125 g/ml, HDL3, d=1.125-1.210 g/ml) by a simple double precipitation method. There was a strong inverse relation between HDL-Cholesterol (HDL-C) and subfractions HDL2-C and HDL3-C with atherosclerosis. This study demonstrated that HDL-C (P<0.001)...

متن کامل

A Cell Culture System for Screening Human Serum for Ability to Promote Cellular Cholesterol Efflux

A cell culture system was employed to test a large number of samples of human serum for the ability to stimulate the efflux of cell cholesterol. The extent of efflux obtained with each specimen was correlated with the serum concentrations of cholesterol, triglycerides, apoprotein (apo) B, apo A-I, apo A-II, and lipoprotein subfractions (ie, high-density lipoprotein2 [HDL2], HDL3, lipoprotein [L...

متن کامل

Conversion of human plasma high density lipoprotein-2 to high density lipoprotein-3. Roles of neutral lipid exchange and triglyceride lipases.

Cholesterol esters accumulating in human plasma high density lipoproteins (HDL) are important in conversion of HDL3 to larger HDL2. We studied whether mechanisms of removal of cholesterol esters from HDL might be important in a reverse direction, i.e. conversion of HDL2 to HDL3. Native HDL2 or HDL3 is incubated with very low density lipoproteins (VLDL) and lipoprotein-poor plasma (d greater tha...

متن کامل

Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells.

Ultracentrifugally isolated high density lipoprotein (HDL) particles of d greater than 1.125 g/ml promote net transport of cholesterol from cultured cells. Consequently, when cultured human fibroblasts and arterial smooth muscle cells were incubated with HDL3 (d = 1.125-1.21 g/ml) and "very high" density lipoprotein (VHDL, d = 1.21-1.25 g/ml), low density lipoprotein (LDL) receptor activity was...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 29 2  شماره 

صفحات  -

تاریخ انتشار 2009