Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin

The concept that hepatic cholesterol synthesis regulates hepatocyte assembl y and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to examine the regulation of a poB secretion by the HMG-CoA reductase inhibitor atorvastatin, ApoB accumul ation in the media was decreased by 24% and 36% at 10 mu M (P < 0.02) and 2 0 mu M (P < 0.01) of atorvastatin, respectively Atorvastatin inhibited HepG 2 cell cholesterol synthesis by up to 96% (P < 0.001) and cellular choleste ryl ester (CE) mass by 54% (P < 0.001), Another HMG-CoA reductase inhibitor , simvastatin, decreased cellular cholesterol synthesis and CE mass by up t o 96% (P < 0.001) and 52% (P < 0.001), respectively However, in con trast t o atorvastatin, simvastatin had no effect on apoB secretion. To characteriz e the reduction in apoB secretion by atorvastatin (10 mu M), pulse-chase ex periments were performed and the kinetic data were analyzed by multicompart mental modeling using SAAM II. Atorvastatin had no affect on the synthesis of apoB, however, apoB secretion into the media was decreased by 44% (P = 0 .048). Intracellular apoB degradation increased proportionately (P 0,048), Simvastatin (10 mu M) treatment did not significantly alter either the secr etion or intracellular degradation of apoB, relative to control. The kineti cs of apoB degradation were best described by a rapidly and a slowly turnin g over degradation compartment, The effect of atorvastatin on apoB degradat ion was largely confined to the rapid compartment, Neither inhibitor affect ed apoB mRNA concentrations, however, both significantly increased LDL rece ptor and HMG-CoA. reductase mRNA levels. Atorvastatin treatment also decrea sed the mRNA for the microsomal triglyceride transfer protein MTP by 22% (P < 0.02). j/r These results show that atorvastatin decreases apoB secretion , by a mechanism that results in an enhanced intracellular degradation of a poB., Differential regulation of apolipoprotein B secretion from HepG2 cell s by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin.