|Le, Ngoc-anh - Emory University|
|Diffenderfer, Margaret - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Thongtang, Nuntakorn - Mahidol University|
|Ooi, Esther - University Of Western Australia|
|Barrett, P. Hugh - University Of Western Australia|
|Horvath, Katalin - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Dolnikowski, Gregory - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Asztalos, Bela - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Schaefer, Ernst - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Brown, W. Virgil - Emory University|
Submitted to: Lipids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/20/2015
Publication Date: 3/26/2015
Citation: Le, N., Diffenderfer, M., Thongtang, N., Ooi, E.M., Barrett, P.R., Horvath, K., Dolnikowski, G.G., Asztalos, B.F., Schaefer, E.J., Brown, W. 2015. Rosuvastatin enhances the catabolism of LDL apoB-100 in subjects with combined hyperlipidemia in a dose dependent manner. Lipids. 50(5):447-458. https://doi.org/10.1007/s11745-015-4005-0.
Interpretive Summary: Elevated plasma concentrations of low density lipoproteins (LDL, "bad cholesterol") and low concentrations of high density lipoproteins (HDL, "good cholesterol") are major independent risk factors for coronary heart disease. Rosuvastatin, which prevents cells in the body from producing cholesterol, is a well-tolerated and highly effective drug that lowers LDL and raises HDL and thereby has therapeutic benefits in reducing the risk of coronary heart disease. The effect of rosuvastatin treatment on LDL cholesterol lowering may depend on the dosage. We studied the way in which rosuvastatin, at very low and very high dosages, affects the production and clearance of apoB-100, the major protein associated with LDL cholesterol. Eight people with elevated LDL cholesterol and triglyceride levels and low HDL cholesterol levels participated in the study. We found that rosuvastatin reduced LDL cholesterol levels by 44% at the low dose and by 54% at the high dose. It also caused a 30% and 36% decrease in plasma apoB-100 levels at the low and the high dose, respectively, due to a dramatic increase in the rate by which apoB-100 was removed from the blood by the liver. It did not change the rate at which apoB-100 lipoproteins are secreted by the liver. Our study indicates that statin therapy, at both the lowest and the highest doses, causes beneficial changes in the LDL cholesterol levels of people at risk for heart disease by increasing the rate at which LDL cholesterol is removed from the blood.
Technical Abstract: Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypothesis was that maximal dose rosuvastatin would decrease the apoB-100 production rate (PR), as well as increase apoB-100 fractional catabolic rate (FCR). Eight subjects received placebo, rosuvastatin 5 mg/day, and rosuvastatin 40 mg/day for 8 weeks each in sequential order. The kinetics of apoB-100 in TRL and LDL and apoA-I in HDL were determined at the end of each phase using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Rosuvastatin at 5 and 40 mg/day decreased LDL cholesterol by 44% and 54% (both P < 0.0001), triacylglycerol by 14% (ns) and 35% (P < 0.01), apoB by 30% and 36% (both P < 0.0001), respectively, and had no significant effects on HDL cholesterol or apoA-I levels. Significant decreases in plasma markers of cholesterol synthesis and increases in cholesterol absorption markers were observed. Rosuvastatin 5 and 40 mg/day increased TRL apoB-100 FCR by 36% and 46% (both ns) and LDL apoB-100 by 63% and 102% (both P < 0.05), respectively. HDL apoA-I PR increased with low dose rosuvastatin (12%, P < 0.05) but not with maximal dose rosuvastatin. Neither rosuvastatin dose altered apoB-100 PR or HDL apoA-I FCR. Our data indicate that maximal dose rosuvastatin treatment in subjects with combined hyperlipidemia resulted in significant increases in the catabolism of LDL apoB-100, with no significant effects on apoB-100 production or HDL apoA-I kinetics.