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Abstract-We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126Ϯ18 mg/dL, meanϮSD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5Ϯ1.7 mg ⅐ kg). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32Ϯ1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9Ϯ2.6 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) and proapoA-I RTs (0.18 and 0.15 versus 0.16Ϯ0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24Ϯ0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7Ϯ0.2 mg ⅐ kg. Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I. (Arterioscler Thromb Vasc Biol. 1998;18:655-664.)

ApoC-I has several different lipid-regulating functions including, inhibition of receptor-mediated uptake of plasma triglyceride-rich lipoproteins, inhibition of cholesteryl ester transfer activity, and mediation of tissue fatty acid uptake. Since little is known about the rate of production and catabolism of plasma apoC-I in humans, the present study was undertaken to determine the plasma kinetics of VLDL and HDL apoC-I using a primed constant (12 h) intravenous infusion of deuterium-labeled leucine. Data were obtained for 14 subjects: normolipidemics (NL, n ‫؍‬ 4), hypertriglyceridemics (HTG, n ‫؍‬ 4) and combined hyperlipidemics (CHL, n ‫؍‬ 6). Plasma VLDL triglyceride ( Our results demonstrate that increased levels of plasma and VLDL apoC-I in hypertriglyceridemic subjects (with or without elevated LDL-C levels) are associated with increased levels of plasma VLDL apoC-I production. -Cohn, J.

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 ؎ 0.9 to 4.3 ؎ 0.2 mg/dl ( Ϫ 38 ؎ 8%, P Ͻ 0.05), predominantly due to a decrease in VLDL apoE (3.4 ؎ 0.8 vs. 1.7 ؎ 0.2 mg/dl; ؊ 42 ؎ 11%) and IDL/LDL apoE (1.9 ؎ 0.3 vs. 0.8 ؎ 0.1 mg/dl; Ϫ 57 ؎ 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 ؎ 0.39 to 3.04 ؎ 0.51 mg/kg/day ( ؊ 34 ؎ 10%, P Ͻ 0.05) and VLDL apoE transport was reduced from 3.82 ؎ 0.67 to 2.26 ؎ 0.42 mg/kg/day ( ؊ 36 ؎ 10%, P ‫؍‬ 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration ( r ‫؍‬ 0.99, P Ͻ 0.001; r ‫؍‬ 0.88, P Ͻ 0.05, respectively, n ‫؍‬ 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia. -Cohn, J. S., M. Tremblay, R. Batal, H. Jacques, L. Veilleux, C. Rodriguez, P. H. R. Barrett, D. Dubreuil, M. Roy, L. Bernier, O. Mamer, and J. Davignon. Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia.

Numerous factors are known to affect the plasma metabolism of HDL, including lipoprotein receptors, lipid transfer protein, lipolytic enzymes and HDL apolipoproteins. In order to better define the role of HDL apolipoproteins in determining plasma HDL concentrations, the aims of the present study were: a ) to compare the in vivo rate of plasma turnover of HDL apolipoproteins [i.e., apolipoprotein A-I (apoA-I), apoC-I, apoC-III, and apoE], and b ) to investigate to what extent these metabolic parameters are related to plasma HDL levels. We thus studied 16 individuals with HDL cholesterol levels ranging from 0.56-1.66 mmol/l and HDL apoA-I levels ranging from 89-149 mg/dl. Plasma kinetics of HDL apolipoproteins were investigated using a primed constant (12 h) infusion of deuterated leucine. Plasma HDL apolipoprotein levels were 41.8 ؎ 1.5, 9.7 ؎ 0.5, 4.9 ؎ 0.5, and 0.7 ؎ 0.1 mol/l for apoA-I, apoC-I, apoC-III and apoE. Plasma transport rates (TRs) were 388.6 ؎ 24.7, 131.5 ؎ 12.5, 66.5 ؎ 9.1, and 31.4 ؎ 3.3 nmol·kg ؊ 1 ·day ؊ 1 ; and residence times (RTs) were 5.1 ؎ 0.4, 3.7 ؎ 0.3, 3.6 ؎ 0.3, and 1.1 ؎ 0.1 days, respectively. HDL cholesterol and apoA-I levels were significantly correlated with HDL apoA-I RT ( r ‫؍‬ 0.69 and r ‫؍‬ 0.56), and were not significantly correlated with HDL apoA-I TR. In contrast, HDL apoC-I, apoC-III, and apoB levels were all positively related to their TRs and not their RTs. HDL apoC-III TR was postively correlated with levels of HDL apoC-III ( r ‫؍‬ 0.73, P Ͻ 0.01), and with those of HDL cholesterol and apoA-I ( r ‫؍‬ 0.54 and r ‫؍‬ 0.53, P Ͻ 0.05, respectively). HDL apoC-III TR was in turn related to HDL apoA-I RT ( r ‫؍‬ 0.51, P Ͻ 0.05). Together, these results provide in vivo evidence for a link between the metabolism of HDL apoC-III and apoA-I, and suggest a role for apoC-III in the regulation of plasma HDL levels. Low plasma levels of HDL are associated with increased risk of coronary heart disease (CHD) (1, 2). A strong therapeutic rationale therefore exists for increasing plasma HDL levels of patients at risk for CHD. An ongoing search for novel therapeutic agents able to increase plasma HDL levels (3) depends on a clear understanding of the many metabolic factors that affect plasma HDL metabolism. These include a ) lipoprotein receptors, e.g., scavenger receptor class B type I (SR-BI) and the adenosine triphosphate binding cassette transporter (ABCA1) (4, 5); b ) lipid transfer proteins, e.g., cholesteryl ester transfer protein and phospholipid transfer protein (6); c ) lipolytic enzymes, e.g., lipoprotein lipase, hepatic lipase (HL), and endothelial lipase (7); and d ) HDL apolipoproteins, e.g., apolipoprotein A-I (apoA-I) and apoA-II (8).Many studies have investigated the physiological role of apolipoproteins that readily exchange between plasma lipoproteins (i.e., apoC-I, apoC-III, and apoE). The majority of this work has focused on the effect of these proteins on triglyceride-rich lipoprotein (TRL) metabolism; however, there is ample evidence that these proteins can ...