scholarly journals The role of the LDL receptor in apolipoprotein B secretion

2000 ◽  
Vol 105 (4) ◽  
pp. 521-532 ◽  
Author(s):  
Jaap Twisk ◽  
Donald L. Gillian-Daniel ◽  
Angie Tebon ◽  
Lin Wang ◽  
P. Hugh R. Barrett ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Ldl Receptor

scholarly journals Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

1986 ◽  
Vol 234 (1) ◽  
pp. 245-248 ◽  
Author(s):  
W Jessup ◽  
G Jurgens ◽  
J Lang ◽  
H Esterbauer ◽  
R T Dean
Keyword(s):  
Apolipoprotein B ◽  
Negative Charge ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Peroxidation Product ◽  
Modified Low Density Lipoproteins ◽  
Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

scholarly journals The role of cyclooxygenase-2 on endurance exercise training in female LDL-receptor knockout ovariectomized mice

2013 ◽  
Vol 85 (3) ◽  
pp. 1157-1164 ◽  
Author(s):  
FLAVIA DE OLIVEIRA ◽  
LAURA B.M. MAIFRINO ◽  
GUSTAVO P.P. DE JESUS ◽  
JULIANA G. CARVALHO ◽  
CLAUDIA MARCHON ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Exercise Training ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cyclooxygenase 2 ◽  
Sedentary Control ◽  
Down Regulation ◽  
Ovariectomized Mice ◽  
Cox 2

Estrogen deprivation in postmenopausal women increases cardiovascular risk. Cardiovascular risk as a result of atherosclerosis is able to induce an inflammatory disease as far as cyclooxygenase-2 ( COX-2) expression. The purpose of the study was to investigate the role of COX-2 on exercise training in female mice low-density lipoprotein receptor knockout ( LDL-KO) with or without ovariectomy. A total of 15 female C57BL/6 mice and 15 female LDL-KO mice were distributed into 6 groups: sedentary control, sedentary control ovariectomized, trained control ovariectomized, LDL-KO sedentary, LDL-KO sedentary ovariectomized and LDL-KO trained ovariectomized. The ascending part of the aorta was stained with H&E and COX-2 expression was assessed by immunohistochemistry. Results revealed that ovariectomy as well as exercise training were not able to induce histopathological changes in mouse aorta for all groups investigated. LDL-KO mice demonstrated plaque containing cholesterol clefts, foamy histiocytes and mild inflammatory process for all groups indistinctly. Ovariectomy induced a strong immunoexpression in atherosclerosis lesion of LDL-KO mice. Nevertheless, a down-regulation of COX-2 expression was detected in LDL-KO trained ovariectomized when compared to LDL-KO sedentary. Our results are consistent with the notion that exercise training is able to modulate COX-2 expression in LDL-KO mice as a result of COX-2 down-regulation.

scholarly journals Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

2020 ◽  
Author(s):  
Li Lin ◽  
Ning Zhou ◽  
Le Kang ◽  
Qi Wang ◽  
Jian Wu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Oxidized Low Density Lipoprotein ◽  
Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

scholarly journals Cholesterol-induced mammary tumorigenesis is enhanced by adiponectin deficiency: role of LDL receptor upregulation

Oncotarget ◽  
2013 ◽  
Vol 4 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
Jing Liu ◽  
Aimin Xu ◽  
Karen Siu-Ling Lam ◽  
Nai-Sum Wong ◽  
Jie Chen ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Mammary Tumorigenesis ◽  
Receptor Upregulation

Abstract 272: Chronic Hyperlipidemia Alters the Population of Endothelial Progenitor Cells in Bone Marrow and Peripheral Circulation via Both ROS-dependent and Independent Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Dylan Z Liu ◽  
Yuqi Cui ◽  
Jason Z Liu ◽  
Lingjuan Liu ◽  
Xin Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Ldl Receptor ◽  
Peripheral Circulation ◽  
Cell Number ◽  
Ros Production ◽  
Endothelial Progenitor ◽  
Ros Formation

Background/Aims: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) make significant contribution to the function and integrity of vasculature. The number of EPCs is significantly decreased in hyperlipidemic patients. Reactive oxygen species (ROS) and oxidative stress were considered an important mechanism for the development of atherosclerosis in hyperlipidemia. The present study was to determine the role of ROS production in the changes of EPC population in chronic hyperlipidemia. Methods and Results: EPC numbers and ROS formation in BM and blood were determined in wild-type (WT) male C57BL/6 mice and hyperlipidemic LDL receptor knockout (LDLR-/-) mice with high fat diet for 4 months. Intracellular blood, extracellular BM and blood ROS production was significantly increased in hyperlipidemic LDLR-/- mice that was effectively blocked with N-acetylcysteine treatment. Hyperlipidemia produced complex changes in EPC populations in BM and blood. The c-Kit+/CD31+ cell number was significantly decreased in BM and blood, and the numbers of CD34+/CD133+ cells and Sca-1+/Flk-1+ cells were significantly decreased in blood without change in BM, which were not affected by inhibition of ROS production. Interestingly, blood CD34+/Flk-1+ cell number was significantly increased in hyperlipidemic mice that was prevented when ROS formation was inhibited. Conclusions: Chronic hyperlipidemia produced significant and complex changes in EPC populations in both BM and circulation through both ROS-dependent and ROS-independent mechanisms in mice.

Abstract 14589: Adiponectin Inhibits Hepatic Production of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both LDL-Receptor Dependent and Independent Mechanisms

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michelle Melone ◽  
Shirya Rashid
Keyword(s):  
Insulin Signaling ◽  
Apolipoprotein B ◽  
Plasma Concentrations ◽  
Ldl Receptor ◽  
Microsomal Triglyceride Transfer Protein ◽  
Human Hepatocytes ◽  
Cellular Expression ◽  
Inflammatory Protein ◽  
Novel Approach ◽  
Obese Human

Background and Rationale: Increasing plasma concentrations of the anti-inflammatory protein, adiponectin, are significantly and independently associated with a lower risk of coronary heart disease (CHD), while hypoadiponectinemia, conversely, is a strong risk factor for CHD. The mechanisms by which adiponectin mediates its cardioprotective role are not clearly understood. Here, we have elucidated a key cause of the cardioprotective effect of adiponectin, involving a direct inhibitory action on hepatic production of pro-atherogenic triglyceride-rich apolipoprotein B (apoB) lipoproteins, mediated through both LDL-receptor dependent mechanisms, involving PCSK9, and LDL-receptor independent mechanisms. Methods and Results: Cultured human hepatocytes (HepG2 cells) and primary human hepatocytes were treated with physiological concentrations of purified recombinant human adiponectin (10 μg/mL) for 24 hours. Adiponectin treatment reduced endogenous apoB cellular expression and secretion markedly by 60% and 30%, respectively, (P<0.01). Adiponectin also reduced apoB production stimulated by prior treatment of cells with oleate or with pro-inflammatory obese human serum (25% reduction for both, P<0.01). Adiponectin-mediated inhibition of cellular apoB production occurred through a substantial increase in levels of hepatocyte LDL-receptors (70%, P<0.01), which promote proteasome-mediated apoB degradation, and which resulted from a 50% reduction in cellular PCSK9 levels (P<0.01 for both). Multiple LDL-receptor independent effects of adiponectin involved mechanisms which reduce cellular apoB stability: (1) a decrease in cellular microsomal triglyceride transfer protein (MTP) (by 25%, (P<0.01); (2) an increase in AMP kinase (by 40%, P<0.01); and (3) marked stimulation of the Akt/Erk insulin signaling pathways. Conclusions: Adiponectin has a direct mitigating effect on hepatic apoB production through mechanisms mediated in part by the LDL-receptor and PCSK9, MTP and the insulin signaling pathway. These findings indicate that that inhibition of apoB may explain in large part adiponectin’s cardioprotective role. Furthermore, targeted adiponectin-based therapies may be a novel approach to inhibit hepatic apoB production.

Abstract 321: LRP6 Regulates LDL Receptor Internalization and LDL Uptake

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Arya Mani ◽  
Gwang-Woong Go ◽  
Zhi-jia Ye ◽  
Rajvir Singh
Keyword(s):  
Cho Cells ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
High Serum ◽  
Skin Fibroblasts ◽  
Receptor Internalization ◽  
Cholesterol Levels ◽  
Endocytic Machinery ◽  
Ldl Uptake

Genetic variations in LRP6 gene are associated with high serum LDL cholesterol levels and atherosclerosis. We examined the role of LRP6 in LDL receptor (LDLR) mediated LDL uptake. LDL uptake was increased when LRP6 was overexpressed and reduced when it was knocked down in LDLR deficient CHO cells. Interestingly, LRP6 knockdown in wildtype CHO cells resulted in a much greater decline in LDL uptake compared to ldlA7 cells. This finding suggested interaction between LRP6 and other proteins involved in LDL uptake. Strikingly, LDL receptor internalization was severely diminished when LRP6 was knocked down and was restored after LRP6 was reintroduced. Further investigations showed that LRP6 forms a complex with the LDL endocytic machinery including LDLR, clathrin and ARH and undergoes endocytosis after stimulation with LDL. LDLR internalization was defective in skin fibroblasts of the LRP6 R611C mutation carriers. LDLR and LRP6 internalizations as well as LDL uptake were significantly impaired in wildtype CHO cells expressing LRP6 R611C mutation(figa,b). These studies introduce LRP6 as a critical modulator of receptor-mediated LDL endocytosis and identify a mechanism by which variation in LRP6 may contribute to high serum LDL levels and atherosclerosis.

scholarly journals Plasma Proprotein Convertase Subtilisin/Kexin Type 9: A Marker of LDL Apolipoprotein B-100 Catabolism?

2009 ◽  
Vol 55 (11) ◽  
pp. 2049-2052 ◽  
Author(s):  
Dick C Chan ◽  
Gilles Lambert ◽  
P Hugh R Barrett ◽  
Kerry-Anne Rye ◽  
Esther M M Ooi ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Experimental Studies ◽  
Ldl Receptor ◽  
Model Assessment ◽  
Proprotein Convertase ◽  
Apo B ◽  
Catabolic Rate ◽  
Wide Range ◽  
Important Regulator ◽  
Kinetics Of

Abstract Background: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. Methods: We used GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. Results: Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol (r = 0.543; P = 0.011), LDL cholesterol (r = 0.543; P = 0.011), apo B-100 (r = 0.548; P = 0.010), and LDL apo B-100 concentrations (r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) (r = −0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. Conclusions: In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.

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