scholarly journals Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

2020 ◽  
Vol 21 (4) ◽  
pp. 1356
Author(s):  
Hassan Nazih ◽  
Jean Marie Bard
Keyword(s):  
Breast Cancer ◽  
Cholesterol Efflux ◽  
Biological Effects ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Growth ◽  
High Growth Rate ◽  
Tumor Formation ◽  
Cholesterol Homeostasis ◽  
Density Lipoprotein Receptor

Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress has been made to treat patients, many questions regarding aspects of this disease relating to carcinogenesis are still open. During carcinogenesis, cells exhibit cholesterol homeostasis deregulation. This results in an accumulation of intracellular cholesterol, which is required to sustain their high growth rate. Cholesterol efflux and influx are two metabolic pathways that are necessary to prevent cholesterol accumulation in the cells. Liver X receptors (LXRs) are nuclear receptors that, upon activation, induce the expression of ABC transporters, responsible for promoting cholesterol efflux, and the expression of IDOL (inducible degrader of low-density lipoprotein receptor), in charge of reducing cholesterol influx. Oxysterols, oxygenated derivatives of cholesterol formed through different pathways, have been discovered as LXR-specific ligands. Some oxysterols are involved in tumor formation while others are considered anti-tumor agents. In the present review, we discuss the involvement of cholesterol, oxysterols and LXRs in breast cancer pathophysiology, with an emphasis on the biological effects of LXR ligands.

Abstract 5: Lipid Droplet Associated Hydrolase: A New Player in Cholesterol Mobilization From Foam Cells

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Younghwa Goo ◽  
Pradip Saha ◽  
Larry Chan ◽  
Antoni Paul
Keyword(s):  
Lipid Droplet ◽  
Cholesterol Efflux ◽  
Bone Marrow Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Cholesterol Homeostasis

Lipid laden macrophages/foam cells are a hallmark of atherosclerotic lesions from early to late stages of development. Macrophages take-up modified low-density lipoprotein (mLDL) particles and store surplus mLDL-derived cholesterol as cholesterol ester (CE) in cytoplasmic lipid droplets (LDs). Accelerating CE hydrolysis from the LDs is a plausible strategy to promote reverse cholesterol transport from the atheroma. However, the identity of the CE hydrolases that function on LDs remains unknown. Previously we identified lipid droplet-associated hydrolase (LDAH) in LDs purified from macrophages and reported that in vitro LDAH regulates CE levels by increasing CE hydrolysis. To determine the relevance of LDAH in atherogenesis, we have generated LDAH knockout (LDAH-/-) mice. Mouse peritoneal macrophages (MPM) isolated from LDAH-/- mice had increased cytoplasmic LDs, increased net CE content, and decreased cholesterol efflux. In atherosclerosis studies, both male and female LDAH-/- mice crossed with apolipoprotein E knockout (apoE-/-) mice fed a Western diet developed larger lesions. Lesions of LDAH-/-/ apoE-/- mice were characterized by increased areas of macrophages containing enlarged cytoplasms with large LDs. Supporting a direct atheroprotective role of LDAH in macrophages, lesions of apoE-/- mice that received bone marrows from LDAH-/-/apoE-/- mice progressed faster than those that received bone marrow cells from LDAH+/+/apoE-/- mice. In qPCR analyses of genes involved in cholesterol homeostasis in macrophages, we found that ABC binding cassette transporters ABCA1 and ABCG1, which mediate cholesterol efflux through the plasma membrane, were consistently decreased in LDAH-/- MPM. Further in vivo gene expression studies on macrophages selectively obtained from lesions using laser capture microdissection are underway. In conclusion, our study suggests that LDAH promotes LD CE hydrolysis and cholesterol efflux from foam cells within the atheroma, and uncovers a potential target to promote reverse cholesterol from arteries as a means of ameliorating atherosclerosis development.

scholarly journals Effect of dietary eicosapentaenoic and docosahexaenoic acid on expression of rat liver genes controlling cholesterol homeostasis and on plasma cholesterol level

2014 ◽  
Vol 59 (No. 9) ◽  
pp. 391-398 ◽  
Author(s):  
T. Komprda ◽  
G. Zorníková ◽  
A. Knoll ◽  
Z. Vykoukalová ◽  
V. Rozíková ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Ldlr Gene ◽  
Expression Of Genes ◽  
Density Lipoprotein Receptor ◽  
Lower Plasma Cholesterol ◽  
Coa Reductase

A hypothesis that eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) lower plasma cholesterol via increased expression of the Insig-1 gene with ensuing decrease of expression of genes coding for 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr) and low density lipoprotein receptor (Ldlr) was tested in rats fed a diet with 3% of fish oil (FO). Expression of the Insig-1 gene in the liver of the FO-fed rats was 730% (P < 0.05) of the control. However, contrary to the hypothesis, expression of the Hmgcr gene and Ldlr gene was 165% and 210% of the control (P > 0.05). Nevertheless, FO in the diet decreased (P < 0.05) plasma cholesterol of rats by 10% (from 1.19 to 1.07 mmol/l); it was therefore concluded that the cholesterol-lowering effect of EPA+DHA is at least partly based on mechanisms other than tested in the present experiment.  

scholarly journals Carvedilol Ameliorates Experimental Atherosclerosis by Regulating Cholesterol Efflux and Exosome Functions

2019 ◽  
Vol 20 (20) ◽  
pp. 5202 ◽  
Author(s):  
Chen ◽  
Tsui ◽  
Chuang ◽  
Chiang ◽  
Chen ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Experimental Atherosclerosis ◽  
Atherosclerotic Cardiovascular Disease ◽  
Beneficial Effects ◽  
Abca1 Expression ◽  
Density Lipoprotein Receptor ◽  
And Function

Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr−/−) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr−/− mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease.

Turnover Rates of the Low-Density Lipoprotein Receptor and PCSK9: Added Dimension to the Cholesterol Homeostasis Model

2021 ◽  
Author(s):  
Mohamad Dandan ◽  
Julia Han ◽  
Sabrina Mann ◽  
Rachael Kim ◽  
Hussein Mohammed ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Lipoprotein Receptor ◽  
Mrna Levels ◽  
Turnover Rates ◽  
Density Lipoprotein Receptor ◽  
Intracellular Cholesterol ◽  
Tissue Cholesterol

Objective: We measured the turnover rates of the LDLR (low-density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type 9) in mice by metabolic labeling with heavy water and mass spectrometry. Approach and Results: In liver of mice fed high-cholesterol diets, LDLR mRNA levels and synthesis rates were markedly lower with complete suppression of cholesterol synthesis and higher cholesterol content, consistent with the Brown-Goldstein model of tissue cholesterol homeostasis. We observed markedly lower PCSK9 mRNA levels and synthesis rates in liver and lower concentrations and synthesis rates in plasma. Hepatic LDLR half-life (t½) was prolonged, consistent with an effect of reduced PCSK9, and resulted in no reduction in hepatic LDLR content despite reduced mRNA levels and LDLR synthesis rates. These changes in PCSK9 synthesis complement and expand the well-established model of tissue cholesterol homeostasis in mouse liver, in that reduced synthesis and levels of PCSK9 counterbalance lower LDLR synthesis by promoting less LDLR catabolism, thereby maintaining uptake of LDL cholesterol into liver despite high intracellular cholesterol concentrations. Conclusions: Lower hepatic synthesis and secretion of PCSK9, an SREBP2 (sterol response element binding protein) target gene, results in longer hepatic LDLR t½ in response to cholesterol feeding in mice in the face of high intracellular cholesterol content. PCSK9 modulation opposes the canonical lowering of LDLR mRNA and synthesis by cholesterol surplus and preserves LDLR levels. The physiological and therapeutic implications of these opposing control mechanisms over liver LDLR are of interest and may reflect subservience of hepatic cholesterol homeostasis to whole body cholesterol needs.

scholarly journals Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression

2020 ◽  
Vol 10 ◽  
Author(s):  
Océane Campion ◽  
Tesnim Al Khalifa ◽  
Benoit Langlois ◽  
Jessica Thevenard-Devy ◽  
Stéphanie Salesse ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Breast Cancer Progression ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Receptor Family

scholarly journals Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice

2012 ◽  
Vol 302 (11) ◽  
pp. L1200-L1208 ◽  
Author(s):  
Monica Goldklang ◽  
Polina Golovatch ◽  
Tina Zelonina ◽  
Jordis Trischler ◽  
Daniel Rabinowitz ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Oxidized Ldl ◽  
Interleukin 1 ◽  
Low Density Lipoprotein ◽  
Airflow Obstruction ◽  
Density Lipoprotein ◽  
Atherogenic Diet ◽  
Lung Damage ◽  
Increased Risk ◽  
Density Lipoprotein Receptor

Smokers with airflow obstruction have an increased risk of atherosclerosis, but the relationship between the pathogenesis of these diseases is not well understood. To determine whether hypercholesterolemia alters lung inflammation and emphysema formation, we examined the lung phenotype of two hypercholesterolemic murine models of atherosclerosis at baseline and on a high-fat diet. Airspace enlargement developed in the lungs of apolipoprotein E-deficient (Apoe −/− ) mice exposed to a Western-type diet for 10 wk. An elevated number of macrophages and lymphocytes accompanied by an increase in matrix metalloproteinase-9 (MMP-9) activity and MMP-12 expression was observed in the lungs of Apoe −/− mice on a Western-type diet. In contrast, low-density lipoprotein receptor-deficient ( Ldlr −/−) mice did not exhibit lung destruction or inflammatory changes. Most importantly, we revealed augmented expression of the downstream targets of the Toll-like receptor (TLR) pathway, interleukin-1 receptor-associated kinase 1, and granulocyte colony-stimulating factor, in the lungs of Apoe −/− mice fed with a Western-type diet. In addition, we demonstrated overexpression of MMP-9 in Apoe −/− macrophages treated with TLR4 ligand, augmented with the addition of oxidized LDL, suggesting that emphysema in these mice results from the activation of the TLR pathway secondary to known abnormal cholesterol efflux. Our findings indicate that, in Apoe −/− mice fed with an atherogenic diet, abnormal cholesterol efflux leads to increased systemic inflammation with subsequent lung damage and emphysema formation.

scholarly journals BLOS1 mediates kinesin switch during endosomal recycling of LDL receptor

2020 ◽  
Author(s):  
Chang Zhang ◽  
Chanjuan Hao ◽  
Guanghou Shui ◽  
Wei Li
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Whole Body ◽  
Cellular Mechanisms ◽  
Anterograde Transport ◽  
Recycling Endosomes ◽  
Endosomal Recycling ◽  
Density Lipoprotein Receptor

AbstractLow-density lipoprotein receptor (LDLR) in hepatocytes plays a key role in normal clearance of circulating LDL and in whole body cholesterol homeostasis. The trafficking of LDLR is highly regulated in clathrin-dependent endocytosis, endosomal recycling and lysosomal degradation. Current studies have been focusing on its endocytosis and degradation. However, the detailed molecular and cellular mechanisms underlying its endosomal recycling are largely unknown. We found that BLOS1, a shared subunit of BLOC-1 and BORC, is involved in LDLR endosomal recycling. Loss of BLOS1 leads to less membrane LDLR and impairs LDL clearance from plasma in hepatocyte-specific BLOS1 knockout mice. BLOS1 interacts with kinesin-3, and that BLOS1 acts as a new adaptor for kinesin-2 to coordinate kinesin-3 and kinesin-2 during the long-range transport of recycling endosomes (REs) to plasma membrane along microtubule tracks to overcome hurdles at microtubule intersections. These findings provide new insights into RE’s anterograde transport and the pathogenesis of dyslipidemia.

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