Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study

Cummings, Michael H.; Watts, Gerald F.; Umpleby, Margot; Hennessy, Thomas R.; Quiney, J; Sönksen, Peter H.

doi:10.1016/0021-9150(94)05430-q

Cited by 63 publications

(36 citation statements)

References 30 publications

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“…Notably, the LDLr has been proposed to promote the presecretory degradation and the reuptake of apoB, in addition to its well-defined role in plasma LDL uptake (25). Furthermore, increased apoB production is observed in FH patients carrying mutations on the LDLr, resulting in a virtual absence of ligand (apoB-100) binding (32,33). Based on these studies, a definitive explanation for the absence of modulation in apoB production despite a sharp decrease in LDLr expression and activity upon PCSK9 infusion in mice remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Lalanne

Lambert

Amar

et al. 2005

Journal of Lipid Research

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Mutations in Proprotein Convertase SubtilisinKexin 9 (PCSK9) have been associated with autosomal dominant hypercholesterolemia. In vivo kinetic studies indicate that LDL catabolism was impaired and apolipoprotein B (apoB)-containing lipoprotein synthesis was enhanced in two patients presenting with the S127R mutation on PCSK9. To understand the physiological role of PCSK9, we overexpressed human PCSK9 in mouse and cellular models as well as attenuated the endogenous expression of PCSK9 in HuH7 hepatoma cells using RNA interference. Here, we show that PCSK9 dramatically impairs the expression of the low density lipoprotein receptor (LDLr) and, in turn, LDL cellular binding as well as LDL clearance from the plasma compartment in C57BL6/J mice but not in LDLr-deficient mice, establishing a definitive role for PCSK9 in the modulation of the LDLr metabolic pathway. In contrast to data obtained in S127R-PCSK9 patients presenting with increased apoB production, our study indicates that wild-type PCSK9 does not significantly alter the production and/or secretion of VLDL apoB in either cultured cells or mice. Finally, we show that unlike PCSK9 overexpression in mice, the S127R mutation in patients led to increased VLDL apoB levels, suggesting a potential gain of function for S127R-PCSK9 in humans.

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Section: Discussionmentioning

confidence: 99%

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Lalanne

Lambert

Amar

et al. 2005

Journal of Lipid Research

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“…The laboratory methods for the study have been fully described elsewhere 27 and are further summarised below.…”

Section: Laboratory Methodsmentioning

confidence: 99%

Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity

et al. 1998

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OBJECTIVE: To test the hypothesis that the hepatic secretion of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) is increased in men with visceral obesity and to examine whether the oversecretion of this apolipoprotein is related to insulin resistance and increased hepatic availability of lipid substrates. SUBJECTS: 16 obese men (body mass index (BMI) b 30 kg/m 2 , waist circumference b 100 cm) and 16 non-obese, age matched men, were studied. MEASUREMENTS: The hepatic secretion of VLDL apoB was measured using a primed (1 mg/kg), constant (1 mg/kg/ h), intravenous infusion of 1-[13 C]-leucine. Isotopic enrichment of VLDL apoB was determined using gas-chromatography mass spectrometry and a multi-compartmental model (SAAM-II) was used to estimate the fractional turnover rate of VLDL apoB. RESULTS: Plasma concentrations of total cholesterol, triglyceride, glucose, insulin, mevalonic acid and lathosterol, as well as dietary fat intake, were signi®cantly higher (P`0.05) in obese than control subjects. The obese subjects had signi®cantly lower high-density-lipoprotein cholesterol (P`0.01). VLDL apoB pool size and hepatic secretion rate (mg/ kg fat free mass/d) were signi®cantly higher in the obese than non-obese subjects (P`0.02). The fractional catabolic rate of VLDL apoB was lower in the obese subjects compared with controls, but the difference did not attain conventional signi®cance (P 0.053). In pooled analysis, there was a signi®cant positive association (P`0.05) between VLDL apoB secretion rate (mg/kg fat free mass/d) and waist-to-hip ratio (WHR), waist circumference, and fasting plasma triglyceride, insulin and glucose concentrations. In multiple linear regression analysis, the association between VLDL apoB secretion and fasting insulin concentration was independent of age, apolipoprotein E (apoE) genotype, mevalonic acid concentration, free fatty acid concentration and fat intake. CONCLUSION: Our ®ndings are consistent with the hypothesis that in visceral obesity, insulin resistance and the associated increased lipid substrate supply to the liver contribute to hepatic oversecretion of apoB; expansion in the VLDL apoB pool size may also be due to a catabolic defect related to insulin resistance.

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“…This sensitization may have little effect on platelets in the circulation as long as the LDL concentration is within the normal range. In contrast, in pathological conditions, such as heterozygous familial hypercholesterolemia, 58 familial combined hyperlipidemia, 59 nephrotic syndrome 60 (1.6 to 2.0 g/L LDL), and especially homozygous familial hypercholesterolemia (3.0 to 5.5 g/L LDL), 61,62 LDL may induce a state of hypersensitivity in the platelets that contributes to the thrombotic tendency observed in these patients.…”

Section: Ldl-induced Fibrinogen Binding and Enhancement Of Collagen-imentioning

confidence: 97%

Low-Density Lipoprotein Enhances Platelet Secretion Via Integrin-α _IIb β ₃ –Mediated Signaling

Hackeng

Huigsloot

Pladet

et al. 1999

ATVB

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Abstract-LDL is known to increase the sensitivity of human platelets for agonists and to induce aggregation and secretion independently at high concentrations, but its mechanism of action is largely obscure. To clarify how LDL increases platelet sensitivity, cells were incubated in lipoprotein-poor plasma and treated with collagen at a concentration that induced Ϸ20% secretion of 14 C-serotonin. Preincubation with LDL (30 minutes at 37°C) enhanced secretion in a dose-dependent manner to 60Ϯ14% at a concentration of 2 g LDL protein/L. Similar stimulation by LDL was seen when secretion was induced by the thrombin receptor-activating peptide. This enhancement was strongly reduced (1)

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Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study

Cited by 63 publications

References 30 publications

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity

Low-Density Lipoprotein Enhances Platelet Secretion Via Integrin-α _IIb β ₃ –Mediated Signaling

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Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study

Cited by 63 publications

References 30 publications

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity

Low-Density Lipoprotein Enhances Platelet Secretion Via Integrin-α IIb β 3 –Mediated Signaling

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Low-Density Lipoprotein Enhances Platelet Secretion Via Integrin-α _IIb β ₃ –Mediated Signaling