Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

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The atherogenicity theory for triglyceride-rich lipoproteins (TRLs; VLDL 1 intermediate density lipoprotein) generally cites the action of apolipoprotein C-III (apoC-III), a component of some TRLs, to retard their metabolism in plasma. We studied the kinetics of multiple TRL and LDL subfractions according to the content of apoC-III and apoE in 11 hypertriglyceridemic and normolipidemic persons. The liver secretes mainly two types of apoB lipoproteins: TRL with apoC-III and LDL without apoC-III. Approximately 45% of TRLs with apoC-III are secreted together with apoE. Contrary to expectation, TRLs with apoC-III but not apoE have fast catabolism, losing some or all of their apoC-III and becoming LDL. In contrast, apoE directs TRL flux toward rapid clearance, limiting LDL formation. Direct clearance of TRL with apoC-III is suppressed among particles also containing apoE. TRLs without apoC-III or apoE are a minor, slow-metabolizing precursor of LDL with little direct removal. Increased VLDL apoC-III levels are correlated with increased VLDL production rather than with slow particle turnover. Finally, hypertriglyceridemic subjects have significantly greater production of apoC-IIIcontaining VLDL and global prolongation in residence time of all particle types. ApoE may be the key determinant of the metabolic fate of atherogenic apoC-III-containing TRLs in plasma, channeling them toward removal from the circulation and reducing the formation of LDLs, both those with apoC-III and the main type without apoC-III.-Zheng, C., C. Khoo, K. Ikewaki, and F. M. Sacks. Epidemiological studies demonstrate that apolipoprotein C-III (apoC-III) and the apoB lipoproteins that have apoC-III as a component independently predict coronary heart disease (1-3). ApoC-III is present on ?40-80% of triglyceride-rich lipoproteins (TRLs) and ?5-10% of LDLs in plasma (4-6). The mechanisms by which apoC-III causes hypertriglyceridemia and atherosclerosis are incompletely understood.Experiments in vitro show that apoC-III can inhibit lipoprotein lipase (7,8) and hepatic lipase (9) and retard the clearance of VLDL by interfering with the binding of apoB-100 (10) or apoE to hepatic receptors (11, 12). Direct evidence supporting a role of high apoC-III level in abnormal TRL metabolism has come from transgenic animal studies. Overexpression of apoC-III in mice causes hypertriglyceridemia (13-17), whereas apoC-III deficiency protects against it (18,19). In these studies, impaired particle clearance via LDL receptors (14-16), reduced binding affinity to cell surface proteoglycans (15, 17), inhibition of lipolysis (17,19), and overproduction of VLDL triglyceride (14, 16) have all been implicated as mechanisms for the hypertriglyceridemic effect of apoC-III. In humans, there is also evidence for apoC-III affecting TRL metabolism. Patients with combined deficiency of apoC-III and apoA-I experience rapid VLDL clearance (20). In a kinetic study, the plasma concentrations and secretion rates of VLDL apoC-III were correlated with those of VLDL triglycerid...

IntroductionLipoprotein(a) (LplaJ) is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL) but contains an additional protein called apolipoprotein(a) (apolal). Apo(a) is highly polymorphic in size, and there is a strong inverse association between the size of-the apo(a) isoform and the plasma concentration of Lp(a). We directly compared the in vivo catabolism of Lp(a) particles containing different size apo(a) isoforms to establish whether there is an effect of apo(a) isoform size on the catabolic rate of Lp(a). In the first series of studies, four normal subjects were injected with radiolabeled S1-Lp(a) and S2-Lp(a) and another four subjects were injected with radiolabeled S2-Lp(a) and S4-Lp(a). No significant differences in fractional catabolic rate were found between Lp(a) particles containing different apo(a) isoforms. To confirm that apo(a) isoform size does not influence the rate of Lp(a) catabolism, three subjects heterozygous for apo(a) were selected for preparative isolation of both Lp(a) particles. The first was a B/S3-apo(a) subject, the second a S4/S6-apo(a) subject, and the third an F/S3-apo(a) subject. From each subject, both Lp(a) particles were preparatively isolated, radiolabeled, and injected into donor subjects and normal volunteers. In all cases, the catabolic rates of the two forms of Lp(a) were not significantly different. In contrast, the allele-specific apo(a) production rates were more than twice as great for the smaller apo(a) isoforms than for the larger apo(a) isoforms. (Lp[a])' is an atherogenic lipoprotein particle in human plasma related in structure to low density lipoproteins (LDL) (1). Elevated plasma Lp(a) concentrations are associated with an increased risk of premature coronary heart disease (CHD) (2-6). Lp(a) levels are predictive ofthe extent of angiographically documented CHD independently of LDL cholesterol levels (7), although the relative risk of elevated Lp(a) concentrations is significantly increased in patients who also have high levels of LDL cholesterol (8, 9). One study estimated that the population attributable risk of CHD due to elevated Lp(a) levels was -25% in men under 60 yr old ( 10). Family studies in a group of 102 probands with premature CHD indicated that Lp(a) excess was the most frequent familial lipoprotein disorder found in this cohort with premature CHD (11). It has been suggested that Lp(a) levels may account for most of the familial predisposition to premature CHD which cannot be accounted for by other known risk factors including LDL and HDL cholesterol levels ( 12). Lp(a) is an LDL-like lipoprotein consisting of lipids and apoB-100, but differs from LDL in that it contains an additional protein called apolipoprotein(a) (apo[a]). Apo(a) is thought to be covalently linked to apoB via a disulfide bridge ( 13,14), but can also associate noncovalently with apoB ( 15, 16). Lp(a) concentrations are strongly genetically determined ( 17), with at least 90% ofthe variation determined by variation within the...

BackgroundEndothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (T2DM). Glucagon like peptide‐1 (GLP‐1) reportedly exerts vasodilatory actions, and inhibitors of dipeptidyl peptidase‐4 (DPP‐4), an enzyme‐degrading GLP‐1, are widely used to treat T2DM. We therefore hypothesized that DPP‐4 inhibitors (DPP‐4Is) improve endothelial function in T2DM patients and performed 2 prospective, randomized crossover trials to compare the DPP‐4I sitagliptin and an α‐glucosidase inhibitor, voglibose (in study 1) and the DPP‐4Is sitagliptin and alogliptin (in study 2).Methods and ResultsIn study 1, 24 men with T2DM (46±5 years) were randomized to sitagliptin or voglibose for 6 weeks without washout periods. Surprisingly, sitagliptin significantly reduced flow‐mediated vasodilatation (FMD; −51% compared with baseline, P<0.05) of the brachial artery despite improved diabetic status. In contrast, voglibose did not affect FMD. To confirm this result and determine whether it is a class effect, we conducted another trial (study 2) to compare sitagliptin and alogliptin in 42 T2DM patients (66±8 years) for 6 weeks with 4‐week washout periods. Both DPP‐4Is improved glycemic control but significantly attenuated FMD (7.2/4.3%, P<0.001, before/after sitagliptin; 7.0/4.8%, P<0.001, before/after alogliptin, respectively). Interestingly, FMD reduction was less evident in subjects who were on statins or whose LDL cholesterol levels were reduced by them, but this was not correlated with parameters including DPP‐4 activity and GLP‐1 levels or diabetic parameters.ConclusionsOur 2 independent trials demonstrated that DPP‐4 inhibition attenuated endothelial function as evaluated by FMD in T2DM patients. This unexpected unfavorable effect may be a class effect of DPP‐4Is.Clinical Trial RegistrationURL: http://center.umin.ac.jp, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).

Deficiency of the cholesteryl ester transfer protein (CETP) in humans is characterized by markedly elevated plasma concentrations of HDL cholesterol and apoA-I. To assess the metabolism of HDL apolipoproteins in CETP deficiency, in vivo apolipoprotein kinetic studies were performed using endogenous and exogenous labeling techniques in two unrelated homozygotes with CETP deficiency, one heterozygote, and four control subjects. All study subjects were administered '3C6-labeled phenylalanine by primed constant infusion for up to 16 h. The fractional synthetic rates (FSRs) of apoA-I in two homozygotes with CETP deficiency (0.135, 0.134 /d) were found to be significantly lower than those in controls (0.196±0.041 /d, P < 0.01).Delayed apoA-I catabolism was confirmed by an exogenous radiotracer study in one CETP-deficient homozygote, in whom the fractional catabolic rate of 125I-apoA-I was 0.139/d (normal 0.216±0.018/d). The FSRs of apoA-II were also significantly lower in the homozygous CETP-deficient subjects (0.104, 0.112/d) than in the controls (0.170±0.023/d, P < 0.01). The production rates of apoA-I and apoA-II were normal in both homozygous CETP-deficient subjects. The turnover of apoA-I and apoA-II was substantially slower in both HDL2 and HDL3 in the CETP-deficient homozygotes than in controls. The kinetics of apoA-I and apoA-II in the CETP-deficient heterozygote were not different from those in controls.These data establish that homozygous CETP deficiency causes markedly delayed catabolism of apoA-I and apoA-II without affecting the production rates of these apolipoproteins. (J.

Lipoprotein(a) (Lp(a)) consists of a low-density lipoprotein-like particle and a covalently linked highly glycosylated protein, called apolipoprotein(a) (apo(a)). Lp(a) derives from the liver but its catabolism is still poorly understood. Plasma concentrations of this highly atherogenic lipoprotein are elevated in hemodialysis (HD) patients, suggesting the kidney to be involved in Lp(a) catabolism. We therefore compared the in vivo turnover rates of both protein components from Lp(a) (i.e. apo(a) and apoB) determined by stable-isotope technology in seven HD patients with those of nine healthy controls. The fractional catabolic rate (FCR) of Lp(a)-apo(a) was significantly lower in HD patients compared with controls (0.164+/-0.114 vs 0.246+/-0.067 days(-1), P=0.042). The same was true for the FCR of Lp(a)-apoB (0.129+/-0.097 vs 0.299+/-0.142 days(-1), P=0.005). This resulted in a much longer residence time of 8.9 days for Lp(a)-apo(a) and 12.9 days for Lp(a)-apoB in HD patients compared with controls (4.4 and 3.9 days, respectively). The production rates of apo(a) and apoB from Lp(a) did not differ significantly between patients and controls and were even lower for patients when compared with controls with similar Lp(a) plasma concentrations. This in vivo turnover study is a further crucial step in understanding the mechanism of Lp(a) catabolism: the loss of renal function in HD patients causes elevated Lp(a) plasma levels because of decreased clearance but not increased production of Lp(a). The prolonged retention time of Lp(a) in HD patients might importantly contribute to the high risk of atherosclerosis in these patients.