Prolonged inhibition of cholesterol synthesis by atorvastatin inhibits apo B-100 and triglyceride secretion from HepG2 cells.
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.
Funatsu
T
T
Pharmacology Laboratory, Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba-shi, Ibaraki 3058585, Japan. funatsu@yamanouchi.co.jp
Suzuki
K
K
Goto
M
M
Arai
Y
Y
Kakuta
H
H
Tanaka
H
H
Yasuda
S
S
Ida
M
M
Nishijima
S
S
Miyata
K
K
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism*; D000069059:Atorvastatin; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D015536:Down-Regulation; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism*
D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D006538:Heptanoic Acids; D011758:Pyrroles; D014280:Triglycerides; D002784:Cholesterol; D000069059:Atorvastatin