Inhibition of HMG-CoA Reductase by Atorvastatin Decreases Both VLDL and LDL Apolipoprotein B Production in Miniature Pigs

Abstract

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) apolipoprotein B (apoB) secretion into the plasma, (2) reduce the conversion of VLDL apoB to LDL apoB, and (3) reduce LDL apoB direct synthesis. ApoB 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. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL cholesterol, total triglyceride, and VLDL triglyceride concentrations by 16%, 31%, 19%, and 28%, respectively (P < .01). Autologous 131I-VLDL, 125I-LDL, and [3H]leucine were injected simultaneously into each pig, and apoB kinetic data were analyzed using multicompartmental analysis (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 VLDL 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 pool size decreased by 30% (4.74 versus 6.75 mg/kg; P = .0004), which was due 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 assay 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 atorvastatin reduces both VLDL and LDL apoB concentrations, primarily by decreasing 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.

The HMG-CoA Reductase Inhibitor Atorvastatin Increases the Fractional Clearance Rate of Postprandial Triglyceride-Rich Lipoproteins in Miniature Pigs

“…We have demonstrated previously in miniature pigs that atorvastatin treatment decreases fasting cholesterol, triglyceride, and VLDL triglyceride concentrations in plasma 36 ; similar responses have been reported in human subjects. [33][34][35] In the present study, decreases were seen in postprandial TRL cholesterol, triglyceride, and RP concentrations.…”

“…These pigs represent a subset of those reported previously. 36 The 2 protocols were performed 1 week apart.…”

“…31,32 Clinical trials of atorvastatin in humans have demonstrated marked plasma LDL cholesterol and triglyceride reductions. [33][34][35] We have previously shown in vivo that inhibition of HMG-CoA reductase by atorvastatin in miniature pigs significantly decreases hepatic apoB-containing lipoprotein secretion into plasma in the fasting state, 36 with minimal effect on rate of clearance. We have now developed a multicompartmental model of TRL metabolism and have used kinetic analysis to determine the metabolic parameters of postprandial exogenous TRL in plasma with atorvastatin treatment.…”

3-Hydroxy-3-Methylglutaryl CoA Reductase Inhibitor Retards Chicken Embryonic Growth

“…In contrast, VLDL in embryonic circulation contains intact apoB-100 suggesting that apoB-100 is synthesized in the embryo (Hermann et al, 2000). It was reported that inhibition of HMG-CoA reductase by atorvastatin decreases VLDL apoB production in miniature pigs (Burnett et al, 1997). In the present study, in ouo pravastatin injection might inhibit synthesis of apoB-100 and decrease transportation of VLDL to the embryo.…”

“…There is a possibility that hepatic cholesterol content in chick embryos may be altered by in ouo injection of statins since cholesterol is continuously being synthesized in the chick embryo (Shand et al, 1994). In addition, inhibition of hepatic HMG-CoA reductase by atorvastatin reduced both VLDL and apoB production in miniature pigs (Burnett et al, 1997). This decreasein apoB secretion by atorvastatin may, in part, be due to a reduction in apoB mRNA abundance.…”