Attenuation of plasma low density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low density lipoprotein receptors

Low density lipoprotein (LDL) reduction indepetl- dent of LDL receptor regulation was investigated using HMG- CoA reductase inhibitors in LDL, receptor-deficient mice. In males, LDL cholesterol dose-dependently decreased with atorvastatin treatment after 1 week. As untreated mice grew older, their LDL cholesterol progressively rose above basal levels, but was quelled with atorvastatin treatment. In females, atorvastatin treatment time-dependently decreased LDI. cho- lesterol levels and induced hepatic HMCXoA reductase activ- ity. Unlike males, cholesterol-lowering effects of the drug were sustained in females. Lovastatin, simvastatin, and prav- astatin also reduced total and LDL, cholesterol; however, addi- tional studies in females demonstrated that atorvastatin caused the greatest dose-dependent and sustained efyect after 2 weeks. In females, hepatic HMGCoA reductase IIIRNA in- versely correlated with LDL cholesterol lowering, with ator- vastatin showing the greatest increase in mRNA levels (17.2- fold), followed by lovastatin (10.7-folti), simvastatin (4.1-fold), and pravastatin (2.5-fold). Atorvastatin effects on lipoprotein production were determined after acute (1 day) or chronic (2 week) treatment prior to intraperitoneal injection of Triton WR1339. Acute treatment reduced cholesterol (-29%) ant1 apoB (- 16%) secretion, with no change in triglyceride secre- tion. In rontrast, chronic treatment elevated cholesterol (+20%), apoB (+310/0), and triglyceride (+57%) secretion. Despite increased cholesterol and apoB secretion, plasma le^- els were reduced by 51% and 46%, respectively. Ovcrall, under acute or chronic conditions, apoB paralleled choles- terol secretion rates, and triglyceride to cholcstc~-ol secrction ratios were elevated by 88% and 32%, respectively. we. pro- pose that atorvastatin limits cholesterol for lipoprotein assem- bly, which is compensated for by triglyceride enrichment. In addition, with either acute or chronic atorvaslatin treatment, apoB-100 secretion was blockcd, and compensated for by an increased secretion of apoB-48. The apoB-48 particles pro- duced arc cleared by LDL, receptor-indeperldent mecha- tlisms, with an overall effect of reducing LDI, production ill these 1nice.m These studies suppor~ the idea that HM(;-<:oA reductase inhibitors modulate lipoprotein levcls indepentie~rt of I,DI, receptors, and suggest thry tnay havc utility in 11ypc1.-