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

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (243.0%), LDL-C (253.6%), and triglycerides (244.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (248.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (238.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r 5 0.85; P , 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.-Tremblay, A. J., B. Lamarche, J-C. Hogue, and P. Couture. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J. Lipid Res.

Section: Discussionsupporting

confidence: 80%

Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia

Tremblay

Lamarche

Hogue

et al. 2009

“…This is supported by in vivo stable isotope studies in patients with combined hyperlipidemia (37). Atorvastatin improves the clear- ance of chylomicron remnants, but it does not have an effect on the production of intestinal lipoproteins, e.g., chylomicrons (38)(39)(40). In our FCHL patients, atorvastatin lowered fasting plasma TG, cholesterol, and apoB.…”

Section: Discussionsupporting

confidence: 67%

Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia

Verseyden

Meijssen

Dijk

et al. 2003

The diagnosis is based on clinical criteria such as the presence of "multiple-type hyperlipidemia," increased plasma apolipoprotein B (apoB), and a positive family history of premature coronary heart disease (CHD) (1-10). Abdominal obesity and increased body mass index (BMI) have been identified as independent factors for the development of hyperlipidemia and CHD in FCHL (4,8,(10)(11)(12). Associations with the complement system have also been reported (13,14). The genetic basis of FCHL has not been elucidated, although several groups have provided evidence suggesting that different genes are involved in the pathogenesis of this disorder (15-23).Impaired FFA metabolism in the postprandial as well as in the postabsorptive period is closely related to the expression of the FCHL phenotype (24-28). FCHL patients have increased postprandial FFA concentrations, compared with healthy controls (24,26,27). Increased postprandial FFA concentrations result in an increased postprandial hepatic FFA flux, which could explain in part the well-known VLDL overproduction in FCHL (26). More recently, an impaired postprandial complement component 3 (C3) response has been associated with the disturbed postprandial FFA handling (27).In vitro and in vivo experiments have demonstrated that the uptake of FFA by peripheral cells is stimulated by acylation-stimulating protein (ASP) (29, 30), which is one of the immunologically inactive cleavage products of C3 (30). Different studies in FCHL and non-FCHL subjects have shown a strong correlation between fasting C3 concentrations and fasting lipid parameters, especially plasma triglycerides (TGs) (13,14,27,31,32). Furthermore, C3 is a powerful indicator for the risk of myocardial infarction in men (32), and recently, it has been shown that C3 depositions are found predominantly in ruptured atherosclerotic plaques in humans (33), suggesting a pathogenetic involvement in the process of atherosclerosis and acute coronary syndromes. Moreover, both fasting and post-

“…In some cases, reduction of hepatic cholesterol levels decreases only the number and not the cholesterol or TG content of secreted VLDL particles. This has been shown in miniature pigs (44) and apoE*3-Leiden mice (45) after HMG-CoA reductase inhibition. In hamster hepatocytes in vitro, hepatic CE and hepatic apoB secretion were closely correlated after the addition of statin or ACAT inhibitor plus or minus oleate (46).…”

Section: Discussionmentioning

confidence: 57%

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Basso

Freeman

et al. 2007

We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss from the body and reduce atherosclerosis. To evaluate this hypothesis, we fed low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/ G8-transgenic (ABCG5/G8-Tg)3LDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing ezetimibe to reduce intestinal cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, and increased (4.4-fold) de novo hepatic cholesterol synthesis versus LDLr-KO mice. Plasma lipids decreased (total cholesterol, 32%; cholesteryl ester, 32%; free cholesterol, 30%), mostly as a result of reduced non-high density lipoprotein-cholesterol and apolipoprotein B (apoB; 36% and 25%, respectively). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/ G8-Tg3LDLr-KO mice. Kinetic studies revealed similar 125 I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-Tg3LDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-Tg3LDLr-KO versus LDLr-KO mice fed the Western/ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and