Jr. Burnett et al., INHIBITION OF HMG-COA REDUCTASE BY ATORVASTATIN DECREASES BOTH VLDL AND LDL APOLIPOPROTEIN-B PRODUCTION IN MINIATURE PIGS, Arteriosclerosis, thrombosis, and vascular biology, 17(11), 1997, pp. 2589-2600
In the present studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG
-CoA) reductase inhibitor atorvastatin was used to test the hypothesis
that inhibition of cholesterol biosynthesis in vivo with a consequent
reduction in the availability of hepatic cholesterol for lipoprotein
synthesis, would (1) reduce very low density lipoprotein (VLDL) apolip
oprotein B (apoB) secretion into the plasma, (2) reduce the conversion
of VLDL apoB to LDL apoB, and (3) reduce LDL apoB direct synthesis. A
poB kinetic studies were carried out in six control miniature pigs and
in six animals after 21 days of administration of atorvastatin (3 mg/
kg per day). Pigs were fed a fat- (34% of calories; polyunsaturated to
monounsaturated to saturated ratio, 1:1:1) and cholesterol- (400 mg/d
cholesterol; 0.1%; 0.2 mg/kcal) containing pig chow-based diet. Atorv
astatin treatment significantly reduced plasma total cholesterol, LDL
cholesterol, total triglyceride, and VLDL triglyceride concentrations
by 16%, 31%, 19%, and 28%, respectively (P<.01). Autologous I-131-VLDL
, I-125-LDL, and [H-3]leucine were injected simultaneously into each p
ig, and apoB kinetic data were analyzed using multicompartmental analy
sis (SAAM II). The VLDL apoB pool size decreased by 29% (0.46 versus 0
.65 mg/kg; P=.002), which was entirely due to a 34% reduction in the V
LDL apoB production rate (PR) (1.43 versus 2.19 mg/kg per hour; P=.027
). The fractional catabolic rate (FCR) was unchanged. The LDL apoB poo
l size decreased by 30% (4.74 versus 6.75 mg/kg; P=.0004), which was d
ue to a 22% reduction in the LDL apoB PR (0.236 versus 0.301 mg/kg per
hour; P=.004), since the FCR was unchanged. The reduction in LDL apoB
PR was primarily due to a 34% decrease in conversion of VLDL apoB to
LDL apoB; however, this reduction was not statistically significant (P
=.114). Hepatic apoB mRNA abundance quantitated by RNase protection as
say was decreased by 13% in the atorvastatin-treated animals (P=.003).
Hepatic and intestinal LDL receptor mRNA abundances were not affected
. We conclude that inhibition of hepatic HMG-CoA reductase by atorvast
atin reduces both VLDL and LDL apoB concentrations, primarily by decre
asing apoB secretion into the plasma and not by an increase in hepatic
LDL receptor expression. This decrease in apoB secretion may, in part
, be due to a reduction in apoB mRNA abundance.