Comparative reactivity of remnant-like lipoprotein particles (RLP) and low-density lipoprotein (LDL) to LDL receptor and VLDL receptor: Effect of a high-dose statin on VLDL receptor expression

Abstract We used a fluorescence flow cytometry assay with a monoclonal low density lipoprotein (LDL) receptor-specific antibody to detect LDL receptor expression on blood T lymphocytes and monocytes. We prepared peripheral blood mononuclear cells from patients with genetically verified LDL receptor-defective (Trp66-Gly mutation, n = 17) or receptor-negative (Trp23-stop mutation, n = 17) heterozygous familial hypercholesterolemia (FH) and from healthy individuals (n = 24). The cells were stimulated to express the maximum amount of LDL receptor by preincubation in lipoprotein-deficient medium. A dual-labeling technique allowed flow cytometric analysis of LDL receptor expression on cells identified by fluorescently conjugated surface marker antibodies. Knowing the LDL receptor gene mutation of the FH patients allowed us to compare the diagnostic capability of this functional assay with the DNA diagnosis and to validate the assay with molecular genetics instead of clinical indices of heterozygous FH. T lymphocytes expressed more LDL receptors and gave better diagnostic results than monocytes, and cells from patients with either the Trp66-Gly or the Trp23-stop mutation had variable but significantly reduced LDL receptor expression. The data indicate that this fluorescence flow cytometry assay is unsuitable for diagnosis of individual cases of heterozygous FH but that it may be useful for functionally characterizing mutations in the LDL receptor gene.

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Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression

Biochemical Journal ◽

10.1042/bj3130873 ◽

1996 ◽

Vol 313 (3) ◽

pp. 873-878 ◽

Cited By ~ 19

Author(s):

Wei LIAO ◽

Mats RUDLING ◽

Bo ANGELIN

Keyword(s):

Time Course ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Expression ◽

Plasma Lipoproteins ◽

Low Density ◽

Mrna Levels ◽

Dependent Manner ◽

Receptor Mrna

Endotoxin induces hyperlipidaemia in experimental animals. In the current study, we investigated whether endotoxin alters hepatic low-density lipoprotein (LDL) receptor expression in rats. Endotoxin treatment suppressed hepatic LDL receptor expression in a dose- and time-dependent manner. Eighteen hours after intraperitoneal injection of increasing amounts of endotoxin, LDL receptor and its mRNA levels were determined by ligand blot and solution hybridization respectively. LDL receptor expression was inhibited by about 70% at a dose of 500 μg/100 g body weight. However, LDL receptor mRNA levels were markedly increased in all endotoxin-treated groups at this time point (by 83–136%; P < 0.001). Time-course experiments showed that LDL receptor expression was already reduced by 48% 4 h after endotoxin injection and was maximally reduced (by 63–65%) between 8 and 18 h. Changes in hepatic LDL receptor mRNA showed a different pattern. By 4 h after endotoxin injection, LDL receptor mRNA had decreased by 78% (P < 0.001). However, by 8 h after endotoxin injection, LDL receptor mRNA had returned to levels similar to controls, and 18 and 24 h after endotoxin injection, they were increased by about 60% (P < 0.05). Separation of plasma lipoproteins by FPLC demonstrated that endotoxin-induced changes in plasma triacylglycerols and cholesterol were due to accumulation of plasma apolipoprotein B-containing lipoproteins among very-low-density lipoprotein, intermediate-density lipoprotein and LDL. It is concluded that endotoxin suppresses hepatic LDL receptor expression in vivo in rats.

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Abstract 398: LDL Receptor Signaling Mediates the Triglyceride-lowering Action of Akkermansia Muciniphila in Genetic Induced Hyperlipidemia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.398 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jing Shen ◽

Xuedong Tong ◽

Neetu Sud ◽

Qiaozhu Su

Keyword(s):

Insulin Sensitivity ◽

Er Stress ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Expression ◽

Low Density ◽

Gi Tract ◽

Metabolic Inflammation ◽

Akkermansia Muciniphila

Akkermansia muciniphila ( A. muciniphila ) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes in mice and humans. The objective of this study was to explore the regulatory effect of A. muciniphila on host lipoprotein metabolism, insulin sensitivity and hepatic metabolic inflammation. By establishing a novel mouse model that colonized the A. muciniphila in the gastrointestinal(GI) tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A. muciniphila in the GI tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared to vehicle-treated mice. A. muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity and prevented overproduction of postprandial chylomicrons in the CREBH-null mice. Mechanistic studies revealed that increased A. muciniphila colonization induced expression of low density lipoprotein (LDL) receptors and apolipoprotein E (apoE) in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate density lipoprotein (IDL) via the mediation of apolipoprotein B100 (apoB) and apoE, leading to the increased clearance of triglyceride-rich very-low-density lipoprotein (VLDL) particles, the precursors of IDLs, from the circulation. Treatment with A. muciniphila further improved hepatic ER stress and metabolic inflammation in CREBH-null mice. Conclusion: Increased colonization of the disease-protective gut bacteria A. muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the LDL receptor expression and alleviating hepatic ER stress and the inflammatory response in CREBH-null mice.

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Modulation of the low-density-lipoprotein-receptor-related protein and its relevance to chylomicron-remnant metabolism

Biochemical Journal ◽

10.1042/bj2880791 ◽

1992 ◽

Vol 288 (3) ◽

pp. 791-794 ◽

Cited By ~ 21

Author(s):

A Szanto ◽

S Balasubramaniam ◽

P D Roach ◽

P J Nestel

Keyword(s):

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Expression ◽

Low Density ◽

Lipoprotein Receptor ◽

Chylomicron Remnant ◽

Related Protein ◽

Density Lipoprotein Receptor ◽

Lipoprotein Receptor Related Protein

Hepatic levels of the low-density-lipoprotein (LDL)-receptor-related protein (LRP) and the LDL receptor were measured in rats subjected to treatments known to affect the expression of the LDL receptor. Propylthiouracil decreased both hepatic LRP and LDL receptor expression by 30-40%. Thyroxine treatment increased LDL receptor levels by 3-fold without altering LRP levels. In contrast, 17 alpha-ethinyloestradiol decreased LRP by 50%, whereas the LDL receptor was increased 5-fold. Plasma chylomicrons and their remnants were decreased to insignificant levels with this treatment. In rats fed with cholesterol there was a significant increase in these particles in plasma (1.21 +/- 0.4 versus 5.71 +/- 0.4 mg/dl), whereas the expression of LRP was unaltered. In Watanabe heritable hyperlipidaemic and cholesterol-fed rabbits, in which the LDL receptor expression is absent or decreased, the expression of LRP was not significantly different from that in normal rabbits. These results suggest that the expression of hepatic LRP can be modulated by changes in the hormonal status of the rat and that this modulation is not tightly co-ordinated with that of the LDL receptor. Moreover, LRP does not appear to have a significant role in chylomicron-remnant clearance, whereas the LDL receptor is actively involved in this process.

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Synthesis and properties of the very-low-density-lipoprotein receptor and a comparison with the low-density-lipoprotein receptor

Biochemical Journal ◽

10.1042/bj3240371 ◽

1997 ◽

Vol 324 (2) ◽

pp. 371-377 ◽

Cited By ~ 13

Author(s):

Dilip D. PATEL ◽

Robert A. FORDER ◽

Anne K. SOUTAR ◽

Brian L. KNIGHT

Keyword(s):

Cho Cells ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Low Density Lipoprotein Receptor ◽

Vldl Receptor ◽

Density Lipoprotein Receptor

The properties of the very-low-density lipoprotein (VLDL) receptor have been studied in Chinese hamster ovary (CHO) cells stably transfected with human VLDL-receptor cDNA and compared with those of the low-density lipoprotein (LDL) receptor expressed under the same conditions. Immunoblotting showed that the cells produced a mature VLDL receptor protein, of apparent Mr 123000 on non-reduced and 158000 on reduced gels, that was less extensively glycosylated than the LDL receptor. The VLDL receptor was more slowly processed than the LDL receptor, with only approx. 70% of the precursor being converted into the mature protein. Nevertheless, the majority of the receptor in the cells was in the mature form, and most of this was present on the cell surface. The human VLDL receptor bound rabbit very-low-density lipoprotein with β electrophoretic mobility (βVLDL), but not human LDL, and uptake through the receptor led to stimulation of oleate incorporation into cholesteryl esters. At 37 °C, the characteristics of VLDL-receptor-mediated uptake and degradation of βVLDL were essentially the same as those mediated by the LDL receptor. However, the VLDL receptor apparently did not show the increase in affinity and decrease in binding of βVLDL on cooling to 4 °C that was exhibited by the LDL receptor. Thus the overexpressed VLDL receptor in CHO cells appears to behave as a lipoprotein receptor with similar, but not identical, properties to the LDL receptor.

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Regulation of plasma LDL: the apoB paradigm

Clinical Science ◽

10.1042/cs20090402 ◽

2009 ◽

Vol 118 (5) ◽

pp. 333-339 ◽

Cited By ~ 28

Author(s):

Allan D. Sniderman ◽

Jacqueline De Graaf ◽

Patrick Couture ◽

Ken Williams ◽

Robert S. Kiss ◽

...

Keyword(s):

Apolipoprotein B ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Critical Aspect ◽

Lipoprotein Particles ◽

Ldl Particles ◽

Plasma Compartment

The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of cholesterol homoeostasis in the hepatocyte. We believe that regulation of cholesterol homoeostasis within the hepatocyte is demonstrably more complex than envisioned by the LDL receptor paradigm, the conventional model to explain the regulation of plasma LDL and the fluxes of cholesterol into the liver, a model which was generated in the fibroblast but has never been fully validated in the hepatocyte. We suggest that the LDL receptor paradigm should be reconfigured as the apoB (apolipoprotein B) paradigm, which states that the rate at which LDL particles are produced is at least an important determinant of their concentration in plasma as the rate at which they are cleared from plasma and that secretion of cholesterol within VLDL (very-low-density lipoprotein) particles is an important mechanism of maintaining cholesterol homoeostasis within the hepatocyte. These two paradigms are not mutually exclusive. The LDL receptor paradigm, however, includes only one critical aspect of the regulation of plasma LDL, namely the rate at which LDL particles are cleared through the LDL receptor pathway, but ignores another – the rate at which LDL particles are added to the plasma compartment. The apoB paradigm includes both and points to a different model of how the hepatocyte achieves cholesterol homoeostasis in a complex metabolic environment.

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Low-density lipoprotein receptors in rat adipocytes: regulation with fasting

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.266.1.e26 ◽

1994 ◽

Vol 266 (1) ◽

pp. E26-E32 ◽

Cited By ~ 3

Author(s):

F. B. Kraemer ◽

C. Laane ◽

B. Park ◽

C. Sztalryd

Keyword(s):

Adipose Tissue ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Expression ◽

Low Density ◽

Fat Cell ◽

Ldl Receptors ◽

Rat Adipocytes ◽

Epididymal Fat

Adipose tissue metabolism is exquisitely sensitive to caloric intake. With increasing adiposity more triglyceride and cholesterol are stored within increasingly large adipocytes, whereas less triglyceride and cholesterol are stored as the size of the fat cell decreases. A portion of the uptake of cholesterol by adipocytes is mediated by low-density lipoprotein (LDL) receptors. The present studies addressed whether LDL receptors are differentially regulated in adipose tissue and the liver during fasting in the rat. Two days of fasting caused a reduction in body weight with an approximately 40% decrease in the epididymal fat depot and fat cell size. No changes in serum cholesterol were noted, but serum triglycerides fell approximately 55% with fasting. LDL receptors detected by immunoblotting decreased progressively with fasting to levels that were 95% below controls in adipocytes isolated from epididymal fat pads by 2-3 days. In contrast, hepatic LDL receptor expression was unaltered by fasting. After 2 days of fasting, the rate of synthesis of LDL receptors in isolated adipose cells was decreased approximately 35%, whereas levels of LDL receptor mRNA were diminished approximately 55%. It is concluded that the expression of LDL receptors in rat adipocytes is markedly downregulated during fasting through transcriptional and posttranscriptional mechanisms. Furthermore, LDL receptor expression is differentially regulated in adipose tissue and liver during fasting in the rat.

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Very low density lipoprotein (VLDL) receptor expression is activated by dexamethasone in a glucocorticoid receptor-dependent manner in adipocytic 3T3-L1 cells

Atherosclerosis ◽

10.1016/s0021-9150(00)81358-1 ◽

2000 ◽

Vol 151 (1) ◽

pp. 299

Author(s):

K. Ensler ◽

B. Angelin ◽

M. Gåfvels

Keyword(s):

Glucocorticoid Receptor ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Receptor Expression ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Dependent Manner ◽

Vldl Receptor

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“Benifuuki” Extract Reduces Serum Levels of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Ligands Containing Apolipoprotein B: A Double-Blind Placebo-Controlled Randomized Trial

Nutrients ◽

10.3390/nu10070924 ◽

2018 ◽

Vol 10 (7) ◽

pp. 924

Author(s):

Masahiro Miyawaki ◽

Hiroyuki Sano ◽

Hisashi Imbe ◽

Reiko Fujisawa ◽

Keiji Tanimoto ◽

...

Keyword(s):

Ldl Cholesterol ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Ice Cream ◽

Serum Levels ◽

High Dose ◽

Low Density ◽

Double Blind

(1) Background: Arteriosclerosis is associated with high levels of low-density lipoprotein (LDL) cholesterol. O-methylated catechins in “Benifuuki” green tea are expected to reduce cholesterol levels, although there is limited research regarding this topic; (2) Methods: This trial evaluated 159 healthy volunteers who were randomized to receive ice cream containing a high-dose of “Benifuuki” extract including 676 mg of catechins (group H), a low-dose of “Benifuuki” extract including 322 mg of catechins (group L), or no “Benifuuki” extract (group C). Each group consumed ice cream (with or without extract) daily for 12 weeks, and their lipid-related parameters were compared; (3) Results: A significant reduction in the level of lectin-like oxidized LDL receptor-1 ligand containing ApoB (LAB) was detected in group H, compared to groups L and C. No significant differences between the three groups were detected in their levels of total cholesterol, triglycerides, and LDL cholesterol; (4) Conclusions: “Benifuuki” extract containing O-methylated catechins may help prevent arteriosclerosis.

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39-kDa receptor-associated protein (RAP) facilitates secretion and ligand binding of extracellular region of very-low-density-lipoprotein receptor: implications for a distinct pathway from low-density-lipoprotein receptor

Biochemical Journal ◽

10.1042/bj3410377 ◽

1999 ◽

Vol 341 (2) ◽

pp. 377-383 ◽

Cited By ~ 3

Author(s):

Atsushi SATO ◽

Yoshimi SHIMADA ◽

Joachim HERZ ◽

Tokuo YAMAMOTO ◽

Hisato JINGAMI

Keyword(s):

Culture Medium ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Receptor Protein ◽

Low Density ◽

Vldl Receptor ◽

Receptor Associated Protein ◽

Extracellular Region ◽

Density Lipoprotein Receptor

We have expressed the extracellular regions of the low-density-lipoprotein (LDL) receptor and the very-low-density-lipoprotein (VLDL) receptor, along with the full-length forms of the receptors, in insect cells in a baculovirus system. The extracellular region of the LDL receptor has been secreted successfully into the culture medium, and it retained the capacities of binding 125I-labelled LDL and β-VLDL. In contrast, the extracellular region of the VLDL receptor remained intracellular and it did not bind 125I-β-VLDL. This difference in expression behaviour between the homologous regions of the two receptors suggests that the two receptor systems are different in receptor-protein maturation or protein targeting. Next we developed the co-expression system with 39-kDa receptor-associated protein (RAP). This co-expression facilitated the secretion of the extracellular region of the VLDL receptor into the culture medium and the secreted receptor bound 125I-β-VLDL. The VLDL receptor remaining intracellular that was co-expressed with RAP also showed binding capacity to 125I-β-VLDL, implying that the existence of RAP prevented receptor-protein aggregation or improved protein-folding status of the truncated VLDL receptor. On the other hand, expression of the extracellular region of the LDL receptor was not facilitated by RAP co-expression. Thus RAP plays an essential role in maintenance of the active conformation and secretion of the extracellular region of the VLDL receptor.

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