Regulation of Hepatic High Density Lipoprotein Binding Protein, HB₂, Expression after Administration of Simvastatin to Rabbits

Abstract

HB₂ a candidate HDL receptor, is quite distinct from other HDL receptors in its structure. However, while changes in cellular cholesterol content, or a reduction in cholesterol biosynthesis accompany corresponding changes in HB₂ expression, the level at which these changes occur have not been determined and the regulation and the function of HB₂ remain uncertain. In order to further investigate the regulation of HB₂, we administered simvastatin to rabbits to reduce cholesterol biosynthesis and follow changes in HB₂ mRNA in various tissues. Six rabbits were given 15 mg/kg of simvastatin by oral administration daily and another six rabbits were given the same volume of saline as a control, for 21 days. They were then sacrificed to obtain samples of blood, liver, lung, jejunum and brain. Simvastatin reduced plasma total cholesterol by 47% and free cholesterol concentrations in liver and lung by 25 and 10%, respectively. Northern blot analysis showed that simvastatin lowered the expression of HB₂ significantly in the liver and lung by 54% and 42% respectively but not in the jejunum or brain. These results support the findings of a previous study showing that HDL binding activity of both HB₁ and HB₂, which was determined by ligand blotting using HDL₃ as a ligand, were reduced after administering cholesterol lowering agents. (Arteriosclerosis, 10 : 1045-1050, 1990). The present study suggests that simvastatin down-regulated HB₂ at the transcriptional stage. Although the complete physiological function of HB₂ is unclear, it appears to play some role in the cholesterol metabolism, warranting further studies to elucidate the nature of this interaction.