Shao-cai Hong1, Shui-ping Zhao, Zhi-hong Wu. 1. Department of Cardiology, The Second Xiangya Hospital of Central South University, Middle Ren-Min Road No.86, Changsha, Hunan 410011, PR China.
Abstract
BACKGROUND: Scavenger receptor class B type I (SR-BI) is a major receptor for high-density lipoproteins (HDL) in the liver. Overexpression of SR-BI attenuated experimental atherosclerosis in murine models, concomitant with a reduction in plasma HDL-cholesterol levels. Probucol is known to be a potent hypolipidemic drug to regress xanthoma formation and carotid atherosclerosis in conjunction with a marked reduction in HDL-cholesterol levels. However, the mechanism by which probucol affects atherosclerosis is not completely understood, and the effect of probucol on the expression of SR-BI was controversial. The aim of this study was to know the effect of probucol on HDL metabolism and SR-BI expression in the liver. METHODS: Sixteen rabbits fed with high cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n = 8): maintained high cholesterol diet for 6 weeks; (2) probucol group (n = 8): the same cholesterol diet plus 1% probucol for 6 weeks. Control group (n = 8) was fed with normal diet for 14 weeks. The classical in situ two steps perfusion of the liver with collagenase IV was used to isolate the parenchymal hepatocytes. The selective uptake of HDL by hepatocytes was performed using the double radiolabelled HDL. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to evaluate SR-BI expression in the liver. RESULTS: Compared with control group, rabbits fed with high cholesterol diet showed higher levels of serum total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and HDL-C, all of which were significantly reduced by probucol treatment. The selective uptake of HDL CEs in probucol group (249.68 +/- 60.13 ng/mg cell protein) was about two folds higher as compared with the control group (122.47 +/- 54.06 ng/mg cell protein, P < 0.01) and high cholesterol group (104.92 +/- 47.91 ng/mg cell protein, P < 0.01), but it could not be reproduced in vitro. The expression of SR-BI were significantly decreased in the high cholesterol group (0.48 +/- 0.06) as compared with control group (0.65 +/- 0.06, P < 0.01). Probucol increased SR-BI expression (0.68 +/- 0.06, P < 0.01) as compared with high cholesterol group. The expression of SR-BI was positively associated with the selective CEs uptake (r = 0.47, P = 0.032). CONCLUSIONS: Probucol up-regulates SR-BI expression and enhance the uptake of HDL CEs by hepatocytes, which may help us to understand the anti-atherogenic properties and the HDL-C-lowering effect of probucol.
BACKGROUND:Scavenger receptor class B type I (SR-BI) is a major receptor for high-density lipoproteins (HDL) in the liver. Overexpression of SR-BI attenuated experimental atherosclerosis in murine models, concomitant with a reduction in plasma HDL-cholesterol levels. Probucol is known to be a potent hypolipidemic drug to regress xanthoma formation and carotid atherosclerosis in conjunction with a marked reduction in HDL-cholesterol levels. However, the mechanism by which probucol affects atherosclerosis is not completely understood, and the effect of probucol on the expression of SR-BI was controversial. The aim of this study was to know the effect of probucol on HDL metabolism and SR-BI expression in the liver. METHODS: Sixteen rabbits fed with high cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n = 8): maintained high cholesterol diet for 6 weeks; (2) probucol group (n = 8): the same cholesterol diet plus 1% probucol for 6 weeks. Control group (n = 8) was fed with normal diet for 14 weeks. The classical in situ two steps perfusion of the liver with collagenase IV was used to isolate the parenchymal hepatocytes. The selective uptake of HDL by hepatocytes was performed using the double radiolabelled HDL. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to evaluate SR-BI expression in the liver. RESULTS: Compared with control group, rabbits fed with high cholesterol diet showed higher levels of serum total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and HDL-C, all of which were significantly reduced by probucol treatment. The selective uptake of HDL CEs in probucol group (249.68 +/- 60.13 ng/mg cell protein) was about two folds higher as compared with the control group (122.47 +/- 54.06 ng/mg cell protein, P < 0.01) and high cholesterol group (104.92 +/- 47.91 ng/mg cell protein, P < 0.01), but it could not be reproduced in vitro. The expression of SR-BI were significantly decreased in the high cholesterol group (0.48 +/- 0.06) as compared with control group (0.65 +/- 0.06, P < 0.01). Probucol increased SR-BI expression (0.68 +/- 0.06, P < 0.01) as compared with high cholesterol group. The expression of SR-BI was positively associated with the selective CEs uptake (r = 0.47, P = 0.032). CONCLUSIONS:Probucol up-regulates SR-BI expression and enhance the uptake of HDL CEs by hepatocytes, which may help us to understand the anti-atherogenic properties and the HDL-C-lowering effect of probucol.
Authors: Marie L Lindegaard; Christopher A Wassif; Boris Vaisman; Marcelo Amar; Elizabeth V Wasmuth; Robert Shamburek; Lars B Nielsen; Alan T Remaley; Forbes D Porter Journal: Hum Mol Genet Date: 2008-09-05 Impact factor: 6.150