Neoagarooligosaccharides enhance the level and efficiency of LDL receptor and improve cholesterol homeostasis

Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change. Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with the conventional model of cholesterol homeostasis within the liver, but are consistent with a new model of regulation, the multi-channel model, which postulates that different lipoprotein particles enter the hepatocyte by different routes and have different metabolic fates within the hepatocyte. The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.

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Modulation of Rat Liver Regeneration after Partial Hepatectomy by Dietary Cholesterol

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2018.19 ◽

2018 ◽

Vol 61 (1) ◽

pp. 22-28

Author(s):

Pavel Živný ◽

Helena Živná ◽

Vladimír Palička ◽

Lenka Žaloudková ◽

Petra Mocková ◽

...

Keyword(s):

Protein Expression ◽

Dna Synthesis ◽

Liver Regeneration ◽

Total Cholesterol ◽

Dietary Cholesterol ◽

Ldl Receptor ◽

Cholesterol Homeostasis ◽

Serum Total Cholesterol ◽

Receptor Protein ◽

Triglyceride Concentration

Introduction: The aim of study was to evaluate impact of long-term dietary cholesterol overload on the cholesterol homeostasis and liver regeneration. Material and Methods: Serum lipid parameters,14C-cholesterol incorporation, liver DNA synthesis and protein expression was determined in partially hepatectomized (PH) rats fed with a standard (SLD) or hypercholesterolemic (CHOL) diet. Results: 29-day intake of CHOL diet before PH produced increase in serum total cholesterol, LDL lipoprotein, and triglyceride concentration. PH provoked decrease in serum total cholesterol and triglyceride concentration in both groups. PH was associated with increase in serum ALT activity more pronounced in CHOL animals. Hepatic DNA synthesis was increased after PH in both groups, but lower in CHOL. Hypercholesterolemic diet reduced the absorption of radiolabelled cholesterol in intestine and then activity in blood and liver. The14C-cholesterol hepatic activities tend to increase after PH in both groups. CHOL diet produced up-regulation of Acyl-CoA:cholesterol acyltransferase-2 protein expression. PH was associated with increase of LDL receptor and Acyl-CoA:cholesterol acyltransferase-2 protein expression in both dietary groups. Discussion: Liver regeneration after PH is negatively influenced by CHOL diet. The increased uptake of cholesterol in the liver after PH associated with up-regulation of LDL receptor protein expression suggests preferential use of extrahepatic cholesterol by the liver.

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Cholesterol Homeostasis: Role of the LDL Receptor

The FASEB Journal ◽

10.1096/fasebj.9.13.7557029 ◽

1995 ◽

Vol 9 (13) ◽

pp. 1378-1381 ◽

Cited By ~ 5

Author(s):

Norman B. Javitt

Keyword(s):

Ldl Receptor ◽

Cholesterol Homeostasis

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The LDL-Receptor and its Molecular Properties: From Theory to Novel Biochemical and Pharmacological Approaches in Reducing LDL-cholesterol

Current Medicinal Chemistry ◽

10.2174/0929867325666180604114819 ◽

2020 ◽

Vol 27 (2) ◽

pp. 317-333 ◽

Cited By ~ 3

Author(s):

Dimitrios Petroglou ◽

Ilias Kanellos ◽

Christos Savopoulos ◽

Georgia Kaiafa ◽

Anastasios Chrysochoou ◽

...

Keyword(s):

Transmembrane Protein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Therapeutic Agents ◽

Molecular Properties ◽

Cholesterol Homeostasis ◽

Lipid Homeostasis ◽

Pharmacological Interventions ◽

Therapeutic Goals ◽

Pubmed Database

Background: The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a transmembrane protein playing a crucial role in effective lipid homeostasis. Various therapeutic agents have been used in the management of dyslipidemias, however, the outcome of therapeutic target is debated. Objective: The aim of this review is to summarize and fully understand the current concept regarding LDL-R and its molecular properties, metabolic pathway, factors affecting LDL-R activity and all available pharmacological interventions. Additionally, non-lipid related properties of LDL-R are also referred. Methods: Literature from the PubMed database was extracted to identify papers between 1984 to 2017 regarding LDL-R and therapeutic agents on dyslipidemia management. Results: We analyzed basic data regarding agents associated with LDL-R (Sterol Regulating Element-Binding Proteins - SREBPs, Protein ARH, IDOL, Thyroid Hormones, Haematologic Disorders, Protein convertase subtilisin kexintype 9 - PCSK-9, ApoC-III) as well as non-lipid related properties of LDL-R, while all relevant (common and novel) pharmacological interventions (statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and PCSK- 9) are also referred. Conclusion: LDL-R and its molecular properties are involved in lipid homeostasis, so potentially sets the therapeutic goals in cardiovascular patients, which is usually debated. Further research is needed in order to fully understand its properties, as well as to find the potential pharmacological interventions that could be beneficial in cholesterol homeostasis and various morbidities in order to reach the most appropriate therapeutic goal.

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LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclerosis

eLife ◽

10.7554/elife.29292 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 25

Author(s):

Xunde Xian ◽

Yinyuan Ding ◽

Marco Dieckmann ◽

Li Zhou ◽

Florian Plattner ◽

...

Keyword(s):

Inflammatory Responses ◽

Apoptotic Cell ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Vascular Wall ◽

Cholesterol Homeostasis ◽

Cell Surface Receptor ◽

Wide Range ◽

Surface Receptor

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity. Here we used a knockin mouse model to uncover a novel atheroprotective role for LRP1 in macrophages where tyrosine phosphorylation of an NPxY motif in its intracellular domain initiates a signaling cascade along an LRP1/SHC1/PI3K/AKT/PPARγ/LXR axis to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflammatory responses.

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The use of monoclonal antibodies to probe human apolipoprotein B structure and function

Canadian Journal of Biochemistry and Cell Biology ◽

10.1139/o85-112 ◽

1985 ◽

Vol 63 (8) ◽

pp. 906-912 ◽

Cited By ~ 8

Author(s):

Ross W. Milne ◽

Yves L. Marcel

Keyword(s):

Monoclonal Antibodies ◽

Limited Proteolysis ◽

Ldl Receptor ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Lipid Vesicles ◽

Cholesterol Homeostasis ◽

Antigenic Determinants ◽

Lipoprotein Subfractions ◽

Apo B

Apolipoprotein (apo) B plays an important role in plasma lipid transport and in the maintenance of cholesterol homeostasis. Attempts to determine the structure of apo B have been hampered by technical obstacles resulting from its chemical and physical properties. Recently monoclonal antibodies (Mabs) against human apo B have been used as probes to study apo B structure and heterogeneity. Certain Mabs are capable of blocking binding of low density lipoprotein (LDL) apo B to the cell surface LDL receptor, which presumably reflects the proximity of their antigenic determinants to the receptor recognition domain. The distribution of antigenic determinants recognized by Mabs has been studied on the hepatic (apo B-100) and intestinal (apo B-48) forms of apo B and on fragments generated by limited proteolysis of apo B. Some Mabs are specific for apo B-100, whereas others cross-react with apo B-48. Apo B-100 specific Mabs coupled to Sepharose have been used to isolate separately apo-B-containing lipoproteins of intestinal and hepatic origin and their respective lipid and apolipoprotein compositions have been determined. Using the separated fractions it has been shown that apo B-100, but not apo B-48, can react with the LDL receptor. Most Mabs failed to react with apo B which had been delipidated and resolubilized, but in some cases immunoreactivity could be recovered if the solubilized apo B were reincorporated into lipid vesicles. These experiments showed that different determinants had different lipid requirements for their expression. Within an individual there is immunochemical heterogeneity in apo-B-containing lipoproteins in the expression of apo B antigenic determinants which can be detected by Mabs. Intersubject differences in reactivity of lipoprotein subfractions with Mabs have also been observed and in some cases appear to represent genetic polymorphism of apo B.

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High-dose supplemental selenite to male Syrian hamsters fed hypercholesterolaemic diets alters Ldlr, Abcg8 and Npc1l1 mRNA expression and lowers plasma cholesterol concentrations

British Journal Of Nutrition ◽

10.1017/s0007114511005587 ◽

2011 ◽

Vol 108 (2) ◽

pp. 257-266 ◽

Cited By ~ 2

Author(s):

Johanne Poirier ◽

Kevin A. Cockell ◽

Kylie A. Scoggan ◽

W. M. Nimal Ratnayake ◽

Hélène Rocheleau ◽

...

Keyword(s):

Mrna Expression ◽

Plasma Cholesterol ◽

Control Diet ◽

Ldl Receptor ◽

Saturated Fat ◽

Cholesterol Homeostasis ◽

High Dose ◽

Mrna Levels ◽

Syrian Hamsters ◽

Tissue Changes

The aim of the present study was to elucidate possible cholesterol-lowering mechanism(s) of high-dose supplemental Se in the form of selenite, a known hypocholesterolaemic agent. Male Syrian hamsters (four groups, ten per group) were fed semi-purified diets for 4 weeks containing 0·1 % cholesterol and 15 % saturated fat with selenite corresponding to varying levels of Se: (1) Se 0·15 parts per million (ppm), control diet; (2) Se 0·85 ppm; (3) Se 1·7 ppm; (4) Se 3·4 ppm. Lipids were measured in the bile, faeces, liver and plasma. The mRNA expression of several known regulators of cholesterol homeostasis (ATP-binding cassette transporters g5 (Abcg5) and g8 (Abcg8), 7-hydroxylase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, LDL receptor (LdLr) and Nieman-Pick C1-like 1 protein (Npc1l1)) were measured in the liver and/or jejunum. Oxysterols including 24-(S)-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol (27-OHC) were measured in the liver. Significantly lower total plasma cholesterol concentrations were observed in hamsters consuming the low (0·85 ppm) and high (3·4 ppm) Se doses. The two highest doses of Se resulted in decreased plasma LDL-cholesterol concentrations and increased mRNA levels of hepatic Abcg8, Ldlr and jejunal Ldlr. Higher hepatic 27-OHC and TAG concentrations and lower levels of jejunal Npc1l1 mRNA expression were noted in the 1·7 and 3·4 ppm Se-treated hamsters. Overall, Se-induced tissue changes in mRNA expression including increased hepatic Abcg8 and Ldlr, increased jejunal Ldlr and decreased jejunal Npc1l1, provide further elucidation regarding the hypocholesterolaemic mechanisms of action of Se in the form of selenite.

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