Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo

Rensen, Patrick C.N.; Herijgers, N.; Netscher, M.; Meskers, Stefan C. J.; Eck, Miranda Van; Berkel, Theo J.C. Van

doi:10.1016/s0022-2275(20)37190-x

Cited by 156 publications

(35 citation statements)

References 55 publications

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“…Data from rat liver perfusion studies suggest that the size of the remnant particle is an important determinant in receptor recognition (20). This has been confirmed in vivo using apoE-enriched artificial 'neo-chylomicrons' (21). In addition to size, the apoE content of a remnant particle influences receptor specificity.…”

mentioning

confidence: 83%

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

Dijk

Vlijmen

Hof³

et al. 1999

Journal of Lipid Research

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To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes ( Apoe Ϫ / Ϫ ؒ Ldlr Ϫ / Ϫ ) using adenovirusmediated gene transfer. We found that a low level of APOE expression, that was capable of reducing the hyperlipidemia in Apoe Ϫ / Ϫ mice, did not result in a reduction of the hyperlipidemia in Apoe Ϫ / Ϫ ؒ Ldlr Ϫ / Ϫ mice. Surpisingly, a very high level of APOE expression also did not result in a reduction of hypercholesterolemia in Apoe Ϫ / Ϫ ؒ Ldlr Ϫ / Ϫ mice, despite very high levels of circulating apoE ( Ͼ 160 mg/dl). Only a moderately high level of APOE expression resulted in a reduction of serum cholesterol level (from 35.2 ؎ 6.7 to 14.6 ؎ 2.3 mmol/l) and the disappearance of VLDL from the serum. Moreover, the very high level of APOE expression resulted in a severe hypertriglyceridemia in Apoe Ϫ / Ϫ ؒ Ldlr Ϫ / Ϫ mice and not Apoe Ϫ / Ϫ mice (25.7 ؎ 8.9 and 2.2 ؎ 1.8 mmol/l, respectively). This hypertriglyceridemia was associated with an APOE-induced increase in the VLDL triglyceride production rate and an inhibition of VLDL-triglyceride lipolysis. We conclude from these data that, for efficient clearance, the non-LDL receptor-mediated pathway requires a higher level of APOE expression as compared to the LDL receptor, but is more sensitive to an APOE-induced increase in VLDL production and inhibition of VLDL-triglyceride lipolysis. -van Dijk, K.

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mentioning

confidence: 83%

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

Dijk

Vlijmen

Hof³

et al. 1999

Journal of Lipid Research

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“…Indeed, by comparing in vivo kinetics of [ 14 C]CO incorporated in TRL-like particles of different size (i.e., a mean diameter of 45, 75, and 150 nm, respectively), we previously reported that smaller particles are characterized by a slower plasma clearance (Khedoe et al, 2015;Rensen et al, 1997). In addition, the newly prepared particles showed a higher [ 14 C]CO uptake by the spleen, which is likely due to the presence of also large particles in the more heterogeneous emulsion (Khedoe et al, 2015;Rensen et al, 1997). We expect that the minor differences caused by the smaller average particle size and increased heterogeneity of the emulsion particles prepared according to the simplified procedure will have a minimal effect when using them to study TLR metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, by comparing liver uptake of 50 and 150 nm TRLlike particles, contribution of LDLr-dependent and LDLrindependent pathways to liver TRL-remnant clearance can be studied. Unlike the routine procedure which produces three fractions of TRL-like particles with mean diameters of 150, 75, and 50 nm via subsequent steps of density gradient ultracentrifugation (Rensen et al, 1997), the simplified procedure only yields a single particle emulsion, and cannot be used to study the contribution of the LDLr to hepatic TRL-remnant clearance, for example, in context of a PCSK9 inhibitor that specifically increases hepatic LDLr levels (Hoeke, Wang, et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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A simplified procedure to trace triglyceride‐rich lipoprotein metabolism in vivo

et al. 2021

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“…Similarly, infusions of CM-like triglyceride emulsions cause accumulation of VLDL of hepatic origin, because they are degraded by the same pathways (31). Studies related to intravenous CM or CM-like emulsions are mostly rat (9, 10, 21 -23, 26, 27, 32) or mouse experiments (33), but human studies have also been performed (4-6, 8, 31, 34). For example, patients with coronary artery disease have retarded clearance of [ 14 C]cholesteryl ester after an injection of CM-like lipid emulsion (5).…”

Section: Discussionmentioning

confidence: 99%

Fate of intravenously administered squalene and plant sterols in human subjects

Relas

Gylling

Miettinen

2001

Journal of Lipid Research

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We have studied metabolism of plant sterols and squalene administered intravenously in the form of lipid emulsion mimicking chylomicrons (CM). The CM-like lipid emulsion was prepared by dissolving squalene in commercially available Intralipid ® . The emulsion was given as an intravenous bolus injection of 30 ml containing 6.3 mg of cholesterol, 1.9 mg of campesterol, 5.7 mg of sitosterol, 1.6 mg of stigmasterol, 18.1 mg of squalene, and 6 g of triglycerides in six healthy volunteers. Blood samples were drawn from the opposite arm before and serially 2.5-180 min after the injections. The decay of CM squalene, plant sterols, and triglycerides was monoexponential. The half-life of CM squalene was 74 ؎ 8 min, that of campesterol was 37 ؎ 5 min ( P Ͻ 0.01 from squalene), and those of sitosterol, stigmasterol, and triglycerides were 17 ؎ 2, 15 ؎ 1, and 17 ؎ 2 min, respectively ( P Ͻ 0.01 from squalene and campesterol). The CM squalene concentration still exceeded the baseline level 180 min after injection ( P ‫؍‬ 0.02), whereas plant sterols and triglycerides returned to the baseline level between 45 and 120 min after injection. The half-lives of squalene and campesterol were positively correlated with their fasting CM concentrations. In addition, VLDL squalene, campesterol, and triglyceride concentrations, VLDL, LDL, and HDL sitosterol concentrations, as well as VLDL and LDL stigmasterol concentrations were increased significantly. Cholesterol concentrations increased in VLDL ( P Ͻ 0.05), but were unchanged in CM after injection. These data suggest that squalene clearance occurs more slowly than that of plant sterols and triglycerides from CM, and that squalene is more tightly associated with triglyceriderich lipoproteins than are plant sterols in injected CM-like emulsions. -Relas, H., H. Gylling, and T. A. Miettinen. Fate of intravenously administered squalene and plant sterols in human subjects.

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Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo

Cited by 156 publications

References 55 publications

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

A simplified procedure to trace triglyceride‐rich lipoprotein metabolism in vivo

Fate of intravenously administered squalene and plant sterols in human subjects

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