Abstract 322: Effect of Atorvastatin on Very-Low-Density Lipoprotein Triglyceride Kinetics in Obese Men

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Esther M Ooi ◽  
Theodore W Ng ◽  
Gerald F Watts ◽  
Dick C Chan ◽  
Hugh R Barrett
Keyword(s):  
Statistical Significance ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Appreciable Effect ◽  
Fractional Catabolic Rate ◽  
Compartmental Modelling ◽  
Catabolic Rate ◽  
Parallel Group ◽  
Vldl Triglyceride

Background Hypertriglyceridemia is a risk factor for cardiovascular disease. Atorvastatin effectively decreases plasma and VLDL triglyceride concentrations in humans, but the mechanism of action is unknown. This study examined the effect of atorvastatin on VLDL triglyceride (VLDL-TG) metabolism in obese men. Hypothesis: Atorvastatin decreases VLDL-TG concentrations by increasing VLDL-TG catabolism. Methods: 25 obese men (mean ± SEM: age 52 ± 3 years, BMI 34.5 ± 1.4 kg/m 2 , plasma triglyceride 1.9 ± 0.1 mmol/L, HDL cholesterol 1.00 ± 0.05 mmol/L) were studied in a two-arm parallel group study design. Eligible subjects entered a 3 week run-in dietary stabilizing period at the end of which they were randomized to a 6 week treatment period of either atorvastatin 40 mg/day (ATV) or placebo. VLDL-TG kinetics were examined using stable isotope methods and compartmental modelling. Results: ATV decreased plasma TG, VLDL apoB and VLDL apoC-III concentrations compared with placebo (p<0.05). Compared with placebo, ATV decreased VLDL-TG concentration ( ATV vs. placebo) (-40% vs. +2%, p<0.01) and increased VLDL-TG fractional catabolic rate (FCR; +54 % vs. -7%, p<0.01). ATV did not alter VLDL-TG production rate. Change in VLDL-TG concentration was positively correlated with change in VLDL apoB (r = 0.81, p<0.01) and VLDL apoC-III (r = 0.65, p=0.02) concentrations, and negatively correlated with VLDL-TG FCR (r = -0.54, p=0.05). Change in VLDL-TG FCR was negatively correlated with VLDL apoC-III, but this failed to reach statistical significance (r = -0.53, p=0.06). Conclusions: In obese men, ATV decreased plasma and VLDL-TG concentrations chiefly by increasing VLDL-TG catabolism, with no appreciable effect on VLDL-TG synthesis. Our data suggest that reduction in apoC-III concentration with ATV may explain, in part, the increase in VLDL-TG catabolism.

scholarly journals Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism

2003 ◽  
Vol 376 (3) ◽  
pp. 765-771 ◽  
Author(s):  
Andelko HRZENJAK ◽  
Sasa FRANK ◽  
Xingde WO ◽  
Yonggang ZHOU ◽  
Theo van BERKEL ◽  
...  
Keyword(s):  
Physiological Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Asialoglycoprotein Receptor ◽  
Fractional Catabolic Rate ◽  
Wild Type ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
First Time

Lp(a) [lipoprotein (a)] is a highly atherogenic plasma lipoprotein assembled from low-density lipoprotein and the glycoprotein apolipoprotein (a). The rate of Lp(a) biosynthesis correlates significantly with plasma Lp(a) concentrations, whereas the fractional catabolic rate does not have much influence. So far, little is known about Lp(a) catabolism. To study the site and mode of Lp(a) catabolism, native or sialidase-treated Lp(a) was injected into hedgehogs or ASGPR (asialoglycoprotein receptor)-knockout (ASGPR−) mice or wild-type (ASGPR+) mice, and the decay of the plasma Lp(a) concentration was followed. COS-7 cells were transfected with high- (HL-1) and low-molecular-mass ASGPR subunits (HL-2), and binding and degradation of intact or desialylated Lp(a) were measured. In hedgehogs, one of the few species that synthesize Lp(a), most of the Lp(a) was taken up by the liver, followed by kidney and spleen. Lp(a) and asialo-Lp(a) were catabolized with apparent half-lives of 13.8 and 0.55 h respectively. Asialo-orosomucoide increased both half-lives significantly. In mice, the apparent half-life of Lp(a) was 4–6 h. Catabolism of native Lp(a) by wild-type mice was significantly faster compared with ASGPR− mice and there was a significantly greater accumulation of Lp(a) in the liver of ASGPR+ mice compared with ASGPR− mice. The catabolism of asialo-Lp(a) in ASGPR− mice was 8-fold faster when compared with native Lp(a) in wild-type mice. Transfected COS-7 cells expressing functional ASGPR showed approx. 5-fold greater binding and 2-fold faster degradation of native Lp(a) compared with control cells. Our results for the first time demonstrate a physiological function of ASGPR in the catabolism of Lp(a).

scholarly journals Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice

1997 ◽  
Vol 321 (2) ◽  
pp. 445-450 ◽  
Author(s):  
Miek C. JONG ◽  
Janine H. van REE ◽  
Vivian E. H. DAHLMANS ◽  
Rune R. FRANTS ◽  
Marten H. HOFKER ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Fractional Catabolic Rate ◽  
Catabolic Rate ◽  
And Control ◽  
Deficient Mice

The function of apolipoprotein (apo) C1 in vivo is not clearly defined. Because transgenic mice overexpressing human apoC1 show elevated triacylglycerol (TG) levels [Simonet, Bucay, Pitas, Lauer and Taylor (1991) J. Biol. Chem. 266, 8651Ő8654], an as yet unknown role for apoC1 in TG metabolism has been suggested. Here we investigated directly the effect of the complete absence of apoC1 on very-low-density lipoprotein (VLDL)-TG lipolysis, clearance and production, by performing studies with the previously generated apoC1-deficient mice. On a sucrose-rich, low fat/low cholesterol (LFC) diet, apoC1-deficient mice accumulate in their circulation VLDL particles, which contain relatively lower amounts of lipids when compared with VLDL isolated from control mice. Lipolysis assays in vitro on VLDL from apoC1-deficient and control mice showed no differences in apparent Km and Vmax values (0.27ŷ0.06 versus 0.24ŷ0.03 mmol of TG/litre and 0.40ŷ0.03 versus 0.36ŷ0.03 mmol of non-esterified fatty acid (NEFA)/min per litre respectively). To correct for potential differences in the size of the VLDL particles, the resulting Km values were also expressed relative to apoB concentration. Under these conditions apoC1-deficient VLDL displayed a lower, but not significant, Km value when compared with control VLDL (3.44ŷ0.71 versus 4.44ŷ0.52 mmol of TG2/g apoB per litre). VLDL turnover studies with autologous injections of [3H]TG-VLDL in vivo showed that the VLDL fractional catabolic rate (FCR) was decreased by up to 50% in the apoC1-deficient mice when compared with control mice (10.5ŷ3.4 versus 21.0ŷ1.2/h of pool TG). No significant differences between apoC1-deficient and control mice were observed in the hepatic VLDL production estimated by Triton WR139 injections (0.19ŷ0.02 versus 0.21ŷ0.05 mmol/h of TG per kg) and in the extra-hepatic lipolysis of VLDL-TG (4.99ŷ1.62 versus 3.46ŷ1.52/h of pool TG) in vivo. Furthermore, [125I]VLDLŐapoB turnover experiments in vivo also showed a 50% decrease in the FCR of VLDL in apoC1-deficient mice when compared with control mice on the LFC diet (1.1ŷ0.3 versus 2.1ŷ0.1/h of pool apoB). When mice were fed a very high fat/high cholesterol (HFC) diet, the VLDLŐapoB FCR was further decreased in apoC1-deficient mice (0.4ŷ0.1 versus 1.4ŷ0.4/h of pool apoB). We conclude that, in apoC1-deficient mice, the FCR of VLDL is reduced because of impaired uptake of VLDL remnants by hepatic receptors, whereas the production and lipolysis of VLDL-TG is not affected.

scholarly journals Effect of Low-Density Lipoprotein Apheresis on Kinetics of Apolipoprotein B in Heterozygous Familial Hypercholesterolemia1

2001 ◽  
Vol 86 (4) ◽  
pp. 1679-1686
Author(s):  
Cyrille Maugeais ◽  
Khadija Ouguerram ◽  
Regis Frénais ◽  
Pascale Maugère ◽  
Bernard Charbonnel ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Low Density ◽  
Fractional Catabolic Rate ◽  
Ldl Apheresis ◽  
Catabolic Rate ◽  
High Level

The acute reduction of low-density lipoprotein (LDL) cholesterol obtained by LDL-apheresis allows the role of the high level of circulating LDL on lipoprotein metabolism in heterozygous familial hypercholesterolemia (heterozygous FH) to be addressed. We studied apolipoprotein B (apoB) kinetics in five heterozygous FH patients before and the day after an apheresis treatment using endogenous labeling with [2H3]leucine. Compared with younger control subjects, heterozygous FH patients before apheresis showed a significant decrease in the fractional catabolic rate of LDL (0.24 ± 0.08 vs. 0.65 ± 0.22 day−1; P &lt; 0.01), and LDL production was increased in heterozygous FH patients (18.9 ± 7.0 vs. 9.9 ± 4.2 mg/kg·day; P&lt; 0.05). The modeling of postapheresis apoB kinetics was performed using a nonsteady state condition, taking into account the changing pool size of very low density lipoprotein (VLDL), intermediate density lipoprotein, and LDL apoB. The postapheresis kinetic parameters did not show statistical differences compared with preapheresis parameters in heterozygous FH patients; however, a trend for increases in fractional catabolic rate of LDL (0.24 ± 0.08 vs. 0.35± 0.09 day−1; P = 0.067) and the production of VLDL (13.7 ± 8.3 vs. 21.9 ± 1.6 mg/kg·day; P = 0.076) was observed. These results suggested that the marked decrease in plasma LDL obtained a short time after LDL-apheresis is able to stimulate LDL receptor activity and VLDL production in heterozygous FH.

scholarly journals ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia

2021 ◽  
Author(s):  
Laurens F. Reeskamp ◽  
John S. Millar ◽  
Liya Wu ◽  
Hans Jansen ◽  
Dewi van Harskamp ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Human Monoclonal Antibody ◽  
Density Lipoprotein ◽  
Fractional Catabolic Rate ◽  
Homozygous Familial Hypercholesterolemia ◽  
Unique Identifier ◽  
Catabolic Rate ◽  
Before And After

Objective: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5- 2 H 3 )-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. Conclusions: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04722068.

Effect of exogenous estrogens on catabolism of VLDL in cholesterol-fed rabbits

1981 ◽  
Vol 241 (5) ◽  
pp. E372-E377
Author(s):  
R. S. Kushwaha ◽  
W. R. Hazzard
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pool Size ◽  
Estrogen Treatment ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Fractional Catabolic Rate ◽  
Catabolic Rate ◽  
Metabolic Mechanism

To determine the metabolic mechanism of the hypolipidemic response to estrogen in cholesterol-fed rabbits, very low-density lipoprotein (VLDL) apolipoprotein B (apoB) turnover studies were conducted in cholesterol-fed animals with or without estrogen treatment. Autologous VLDL apoB had a more rapid fractional catabolic rate (FCR) in estrogen-treated than in untreated animals, but there was no difference in the radioactivity appearing in the intermediate-(IDL) and low- (LDL) density lipoproteins. Similar differences in the FCR were observed when isologous VLDL from donors in the opposite group was injected, suggesting that estrogen treatment in cholesterol-fed rabbits accelerated the catabolism of cholesterol- and apoE-rich lipoproteins by a mechanism that is not dependent on its conversion to LDL. Furthermore, VLDL apoB from normal untreated donor animals was catabolized more rapidly in the estrogen-treated animals, but most of the radioactivity appeared in LDL in both groups. These observations suggest that estrogen treatment of cholesterol-fed rabbits affected only the efficiency but not the completeness of catabolism of normal VLDL. Thus the catabolism of vLDL in cholesterol-fed animals treated with or without estrogen depended on the composition of VLDL injected and the pool size of plasma VLDL, which was reduced by estrogen treatment.

Very-low-density lipoprotein triglyceride kinetics in acute and chronic carbohydrate-fed rats

1988 ◽  
Vol 255 (3) ◽  
pp. E236-E240 ◽  
Author(s):  
T. Hirano ◽  
J. Mamo ◽  
M. Poapst ◽  
G. Steiner
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Water Control ◽  
Catabolic Rate ◽  
Identical Manner ◽  
Vldl Triglyceride ◽  
Control Plasma ◽  
Drinking Solution

Very-low-density lipoprotein (VLDL)-triglyceride (TG) kinetics were examined in rats maintained on either chow and water (control) or chow and a 10% carbohydrate drinking solution (fructose or glucose). The hexose solutions were available for an acute (16 h) or chronic (14 day) period. The acute fructose (AF), acute glucose (AG), and chronic fructose (CF) groups were hypertriglyceridemic (HTG) compared with control. Plasma TG concentration in chronic glucose (CG)-fed rats was similar to control. VLDL-TG was endogenously radiolabeled in donor rats with [2-3H]-glycerol. The fractional catabolic rate (FCR) was then determined by monitoring the clearance of plasma [3H]VLDL-TG in recipient animals. Donors and recipients were treated in an identical manner. AF and CF groups had an FCR significantly lower than rats given glucose for comparable periods. Both fructose groups and the AG group also had a lower FCR than control. In contrast, FCR in the CG group was significantly higher than controls. TG production rate (TGPR) in both AF and CF fed rats did not significantly differ from controls, suggesting that the HTG observed in these animals was solely from a catabolic defect. AG- and CG-treated glucose animals both had TGPR significantly higher than controls. Therefore, overproduction of VLDL-TG contributed to the HTG associated with this carbohydrate.

Metabolism of apoprotein B in cynomolgus monkey: evidence for independent production of low-density lipoprotein apoprotein B

1983 ◽  
Vol 244 (2) ◽  
pp. E196-E201
Author(s):  
I. J. Goldberg ◽  
N. A. Le ◽  
H. N. Ginsberg ◽  
J. R. Paterniti ◽  
W. V. Brown
Keyword(s):  
Cynomolgus Monkey ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density Lipoproteins ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Fractional Catabolic Rate ◽  
Catabolic Rate ◽  
Apoprotein B ◽  
The Mean

The catabolism of very-low-density lipoprotein apoprotein B and its conversion to low-density lipoprotein was studied in five chow-fed cynomolgus monkeys following injection of radioiodinated homologous very-low-density lipoproteins. The mean (+/- SD) fractional catabolic rate of very-low-density lipoprotein apoprotein B was 0.97 +/- 0.20 h-1 and the mean (+/- SD) production rate was 0.76 +/- 0.20 mg X kg-1 X h-1. The percent of conversion of very-low-density lipoprotein apoprotein B to low-density lipoprotein ranged from 33 to 59%. In separate studies of low-density lipoprotein apoprotein B turnover performed using homologous radiolabeled low-density lipoprotein in five additional animals, the mean (+/- SD) fractional catabolic rate for low-density lipoprotein apoprotein B was 0.050 +/- 0.017 h-1 and the mean (+/- SD) apoprotein B production rate was 0.70 +/- 0.18 mg X kg-1 X h-1. Comparison of the total low-density lipoprotein apoprotein B production with that derived from very-low-density lipoprotein apoprotein B suggested that a large fraction of plasma low-density lipoprotein apoprotein B was derived from a source exclusive of circulating very-low-density lipoprotein apoprotein B. This was confirmed in two animals by simultaneous injection of radiolabeled very-low-density and low-density lipoproteins. Thus, a significant proportion of cynomolgus monkey low-density lipoproteins are produced either by direct hepatic secretion or by rapid conversion of lower-density lipoproteins before they appear in the peripheral circulation.

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