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 independent of LDL receptor re gulation was investigated using HMG-CoA reductase inhibitors in LDL re ceptor-deficient mice. In males, LDL cholesterol dose-dependently decr eased with atorvastatin treatment after 1 week. As untreated mice grew older, their LDL cholesterol progressively rose above basal levels, b ut was quelled with atorvastatin treatment. In females, atorvastatin t reatment time-dependently decreased LDL cholesterol levels and induced hepatic HMG-CoA reductase activity. Unlike males, cholesterol-lowerin g effects of the drug were sustained in females. Lovastatin, simvastat in, and pravastatin also reduced total and LDL cholesterol; however, a dditional studies in females demonstrated that atorvastatin caused the greatest dose-dependent and sustained effect after 2 weeks. In female s, hepatic HMG-CoA reductase mRNA inversely correlated with LDL choles terol lowering, with atorvastatin showing the greatest increase in mRN A levels (17.2-fold), followed by lovastatin (10.7-fold), simvastatin (4.1-fold), and pravastatin (2.5-fold). Atorvastatin effects on lipopr otein production were determined after acute (1 day) or chronic (2 wee k) treatment prior to intraperitoneal injection of Triton WR1339. Acut e treatment reduced cholesterol (-29%) and apoB (-16%) secretion, with no change in triglyceride secretion. In contrast, chronic treatment e levated cholesterol (+20%), apoB (+31%), and triglyceride (+57%) secre tion. Despite increased cholesterol and apoB secretion, plasma levels were reduced by 51% and 46%, respectively. Overall, under acute or chr onic conditions, apoB paralleled cholesterol secretion rates, and trig lyceride to cholesterol secretion ratios were elevated by 38% and 32%, respectively. We propose that atorvastatin limits cholesterol for lip oprotein assembly, which is compensated for by triglyceride enrichment . In addition, with either acute or chronic atorvastatin treatment, ap oB-100 secretion was blocked, and compensated for by an increased secr etion of apoB-48. The apoB-48 particles produced are cleared by LDL re ceptor-independent mechanisms, with an overall effect of reducing LDL production in these mice. These studies support the idea that HMG-CoA reductase inhibitors modulate lipoprotein levels independent of LDL re ceptors, and suggest they may have utility in hyperlipidemias caused b y LDL-receptor disorders.