Atorvastatin is a new
HMG-CoA reductase inhibitor that strongly lowers plasma
cholesterol and
triglyceride (TG) levels in humans and animals. Since previous data indicated that
atorvastatin has prolonged inhibition of hepatic
cholesterol synthesis, we tested whether this longer duration of inhibitory effect on
cholesterol synthesis decreased hepatic
lipoprotein secretion in vitro. We used the HepG2
hepatoma cell line to: (1) determine the time required until levels of secreted
apo B-100 and TG declined significantly, (2) examine the relation to the mass of cellular
cholesteryl ester (CE) and (3) test
microsomal triglyceride transfer protein (MTP) activity which leads to decreased
apo B-100 production. Although
atorvastatin significantly inhibited
cholesterol synthesis in HepG2 cells regardless of
treatment duration (1, 14 or 24 h), it did not inhibit TG synthesis.
Apo B-100 and TG secretion were unchanged after 1-h
atorvastatin treatment, but declined significantly after 24-h treatment.
Atorvastatin treatment also reduced cellular CE mass, exhibiting both time- and dose-dependency.
Mevalonolactone, a product of
HMG-CoA reductase, attenuated the inhibitory effects of
atorvastatin.
Atorvastatin strongly reduced
mRNA levels of MTP, whereas it did not inhibit MTP activity as measured by TG transfer assay between
liposomes.
Simvastatin also induced treatment- and time-dependent reductions in
apo B-100, whereas the MTP inhibitor
BMS-201038 exhibited no time dependency, instead inhibiting this variable even on 1-h treatment. These results indicate that reduced
apo B-100 secretion caused by
atorvastatin is a secondary result owing to decreased
lipid availability, and that
atorvastatin's efficacy depends on the duration of
cholesterol synthesis inhibition in the liver.