scholarly journals CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Gang Wang ◽  
Jiao-Jiao Chen ◽  
Wen-Yi Deng ◽  
Kun Ren ◽  
Shan-Hui Yin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cholesterol Efflux ◽  
Lentiviral Vector ◽  
Macrophage Polarization ◽  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Novel Approach ◽  
Underlying Mechanisms

AbstractC1q tumor necrosis factor-related protein 12 (CTRP12), a conserved paralog of adiponectin, is closely associated with cardiovascular disease. However, little is known about its role in atherogenesis. The aim of this study was to examine the influence of CTRP12 on atherosclerosis and explore the underlying mechanisms. Our results showed that lentivirus-mediated CTRP12 overexpression inhibited lipid accumulation and inflammatory response in lipid-laden macrophages. Mechanistically, CTRP12 decreased miR-155-5p levels and then increased its target gene liver X receptor α (LXRα) expression, which increased ATP binding cassette transporter A1 (ABCA1)- and ABCG1-dependent cholesterol efflux and promoted macrophage polarization to the M2 phenotype. Injection of lentiviral vector expressing CTRP12 decreased atherosclerotic lesion area, elevated plasma high-density lipoprotein cholesterol levels, promoted reverse cholesterol transport (RCT), and alleviated inflammatory response in apolipoprotein E-deficient (apoE−/−) mice fed a Western diet. Similar to the findings of in vitro experiments, CTRP12 overexpression diminished miR-155-5p levels but increased LXRα, ABCA1, and ABCG1 expression in the aortas of apoE−/− mice. Taken together, these results suggest that CTRP12 protects against atherosclerosis by enhancing RCT efficiency and mitigating vascular inflammation via the miR-155-5p/LXRα pathway. Stimulating CTRP12 production could be a novel approach for reducing atherosclerosis.

scholarly journals HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Dan Song ◽  
Ming Guo ◽  
Shuai Xu ◽  
Xiaotian Song ◽  
Bin Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intellectual Development ◽  
Molecular Mechanisms ◽  
Hsp90 Inhibitor ◽  
Pseudouridine Synthase ◽  
Novel Approach ◽  
Cell Metastasis ◽  
Underlying Mechanisms

Abstract Background Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms. Methods We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry. Results Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis. Conclusions The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.

scholarly journals HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders

2013 ◽  
Vol 210 (2) ◽  
pp. 339-353 ◽  
Author(s):  
Emmanuel L. Gautier ◽  
Marit Westerterp ◽  
Neha Bhagwat ◽  
Serge Cremers ◽  
Alan Shih ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Myeloproliferative Disorders ◽  
Tissue Loss ◽  
Human Leukemia ◽  
Glut1 Expression ◽  
Underlying Mechanisms

A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol–raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.

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.

Abstract 260: Apolipoprotein A-I Binding Protein Regulates Macrophage Polarization in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dina A Schneider ◽  
Longhou Fang ◽  
Yury I Miller
Keyword(s):  
Lipid Rafts ◽  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Binding Protein ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Negative Regulator ◽  
High Cholesterol Diet ◽  
Apolipoprotein A ◽  
M1 Macrophage

Our laboratory recently demonstrated that Apolipoprotein A-I Binding Protein (AIBP), an evolutionarily conserved intracellular and secreted protein, mediates cholesterol efflux from endothelial cells, which in turn disrupts lipid rafts and limits angiogenic signaling. Since lipid rafts are implicated in multiple cell signal cascades, to better understand the in vivo role of AIBP our laboratory has generated Apoa1bp -/- mice. The Apoa1bp -/- mice exhibit increased levels of inflammatory cytokines, and have an increased content of M1 macrophages in white adipose tissue in comparison to wild type mice when challenged with a high fat diet. Since AIBP accelerates cholesterol efflux from macrophages to HDL, and vascular lipid accumulation and inflammation are key factors in atherosclerosis, we hypothesized that AIBP is atheroprotective by suppressing macrophage lipid accumulation and inflammatory M1 macrophage polarization. Immunohistochemistry shows that AIBP is present in atherosclerotic lesion macrophages. However, elicited macrophages lacking AIBP expression do not exhibit any impairment in their ability to polarize to M1, suggesting that deficiency in secreted extracellular AIBP may be responsible for the M1 phenotype observed in Apoa1bp -/- mice. Indeed, treating macrophages with recombinant AIBP prior to polarization resulted in suppression of M1 polarization. In a high-cholesterol diet feeding experiment, Apoa1bp -/- Ldlr -/- mice had increased M1 macrophage content in their aorta and aortic root atherosclerotic lesions, as determined by FACS and immunohistochemistry, respectively. In conclusion, AIBP is an important negative regulator of macrophage polarization and lipid accumulation. A better understanding of AIBP’s regulatory functions in the context of atherosclerosis will provide new mechanistic insights and targeted therapies.

Abstract 1721: Deletion of Both Macrophage ABCG1 and ApoE Independently Promotes Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruud Out ◽  
Bart Lammers ◽  
Reeni B. Hildebrand ◽  
Carmel M. Quinn ◽  
David Williamson ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Independent Effect ◽  
High Cholesterol Diet ◽  
Moderate Increase ◽  
Lesion Development ◽  
Macrophage Cholesterol Efflux ◽  
Atherosclerotic Lesion Development

Objective ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein E (apoE) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. Although a possible interaction between ABCG1 and apoE in cholesterol efflux was postulated, the combined action of these proteins in atherosclerosis is still unclear. Methods and Results LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCG1/apoE double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls. After feeding a high-fat/high-cholesterol diet for 6 weeks, no differences were found in serum lipid levels. However, the mean atherosclerotic lesion area in dKO transplanted animals (187 ± 18 × 10 3 μ m 2 ) was 1.4-fold (p < 0.01) increased compared to single knockouts (ABCG1 KO: 138 ± 5 × 10 3 μm 2 ; apoE KO: 131 ± 7 × 10 3 μm 2 ) and 1.9-fold (p< 0.001) as compared to WT controls (97 ± 15 × 10 3 μm 2 ). In vitro cholesterol efflux experiments confirmed that combined deletion of ABCG1 and apoE resulted in a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Deletion of macrophage ABCG1 or apoE does lead to a moderate increase in atherosclerotic lesion development while combined deletion of ABCG1 and apoE induces a more dramatic increase in atherosclerosis. These results indicate an added, independent effect for both macrophage ABCG1 and apoE in atherosclerosis.

Synthesis of recombinant high density lipoprotein with apolipoprotein A-I and apolipoprotein A-V

2011 ◽  
Vol 392 (5) ◽  
Author(s):  
Xinbo Zhang ◽  
Baosheng Chen
Keyword(s):  
High Density Lipoprotein ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
High Density ◽  
Over Expression ◽  
Apolipoprotein A ◽  
Atherosclerotic Lesion Development

Abstract It has been shown that apolipoprotein A-V (apoA-V) over-expression significantly lowers plasma triglyceride levels and decreases atherosclerotic lesion development. To assess the feasibility of recombinant high density lipoprotein (rHDL) reconstituted with apoA-V and apolipoprotein A-I (apoA-I) as a therapeutic agent for hyperlipidemic disorder and atherosclerosis, a series of rHDL were synthesized in vitro with various mass ratios of recombinant apoA-I and apoA-V. It is interesting to find that apoA-V of rHDL had no effect on lipoprotein lipase (LPL) activation in vitro and very low density lipoprotein (VLDL) clearance in HepG2 cells and in vivo. By contrast, LPL activation and VLDL clearance were inhibited by the addition of apoA-V to rHDL. Furthermore, the apoA-V of rHDL could not redistribute from rHDL to VLDL after incubation at 37°C for 30 min. These findings suggest that an increase of apoA-V in rHDL could not play a role in VLDL clearance in vitro and in vivo, which could, at least in part, attribute to the lost redistribution of apoA-V from rHDL to VLDL and LPL binding ability of apoA-V in rHDL. The therapeutic application of rHDL reconstituted with apoA-V and apoA-I might need the construction of rHDL from which apoA-V could freely redistribute to VLDL.

LILRB4 deficiency aggravates the development of atherosclerosis and plaque instability by increasing the macrophage inflammatory response via NF-κB signaling

2017 ◽  
Vol 131 (17) ◽  
pp. 2275-2288 ◽  
Author(s):  
Zhou Jiang ◽  
Juan-Juan Qin ◽  
Yaxing Zhang ◽  
Wen-Lin Cheng ◽  
Yan-Xiao Ji ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Plaque Instability ◽  
Atherosclerotic Lesions ◽  
Bone Marrow Derived Cells ◽  
Underlying Mechanisms ◽  
Human And Mouse

Atherosclerosis is a chronic inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is associated with the pathological processes of various inflammatory diseases. However, the potential function and underlying mechanisms of LILRB4 in atherogenesis remain to be investigated. In the present study, LILRB4 expression was examined in both human and mouse atherosclerotic plaques. The effects and possible mechanisms of LILRB4 in atherogenesis and plaque instability were evaluated in LILRB4-/-ApoE-/- and ApoE-/- mice fed a high-fat diet (HFD). We found that LILRB4 was located primarily in macrophages, and its expression was up-regulated in atherosclerotic lesions from human coronary arteries and mouse aortic roots. LILRB4 deficiency significantly accelerated the development of atherosclerotic lesions and increased the instability of plaques, as evident by the increased infiltration of lipids, decreased amount of collagen components and smooth muscle cells. Moreover, LILRB4 deficiency in bone marrow derived cells promoted the development of atherosclerosis. In vivo and in vitro analyses revealed that the proinflammatory effects of LILRB4 deficiency were mediated by the increased activation of NF-κB signaling due to decreased src homolog 2 domain containing phosphatase (Shp) 1 phosphorylation. In conclusion, the present study indicates that LILRB4 deficiency promotes atherogenesis, at least partly, through reduced Shp1 phosphorylation, which subsequently enhances the NF-κB-mediated inflammatory response. Thus, targetting the ‘LILRB4-Shp1’ axis may be a novel therapeutic approach for atherosclerosis.

scholarly journals New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals:In VitroandIn VivoStudies and the Underlying Mechanisms

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Madhulika Singh ◽  
Shankar Suman ◽  
Yogeshwer Shukla
Keyword(s):  
Skin Cancer ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cancer Chemoprevention ◽  
Chemopreventive Agents ◽  
Novel Approach ◽  
Comprehensive Knowledge ◽  
Underlying Mechanisms

Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenicin vitroandin vivomodels and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer.

scholarly journals Terminalia bellirica Extract Inhibits Low-Density Lipoprotein Oxidation and Macrophage Inflammatory Response in Vitro

Antioxidants ◽  
2016 ◽  
Vol 5 (2) ◽  
pp. 20 ◽  
Author(s):  
Miori Tanaka ◽  
Yoshimi Kishimoto ◽  
Emi Saita ◽  
Norie Suzuki-Sugihara ◽  
Tomoyasu Kamiya ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Oxidation ◽  
Terminalia Bellirica ◽  
Low Density Lipoprotein Oxidation

Improved Measurement of Low-Density-Lipoprotein Susceptibility to Copper-Induced Oxidation: Application of a Short Procedure for Isolating Low-Density Lipoprotein

1992 ◽  
Vol 38 (10) ◽  
pp. 2066-2072 ◽  
Author(s):  
H A Kleinveld ◽  
H L Hak-Lemmers ◽  
A F Stalenhoef ◽  
P N Demacker
Keyword(s):  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Thiobarbituric Acid ◽  
Lag Time ◽  
Butylated Hydroxytoluene ◽  
Ldl Oxidation ◽  
Low Density ◽  
Short Run

Abstract Low-density-lipoprotein (LDL) oxidation may provide the crucial link between plasma LDL and atherosclerotic-lesion formation. Oxidation can be induced in vitro by incubating LDL with cells or metal ions and can be measured by continuously monitoring conjugated-diene absorbance at 234 nm. Measurement of LDL oxidizability was improved by performing the assay with 0.05 g of LDL-protein per liter of phosphate buffer containing 1 mumol of EDTA, by initiating oxidation by adding CuCl2 (5 mumol/L) at 30 degrees C, and by using a short-run ultracentrifugation method for isolating LDL, which reduced the time needed for obtaining purified LDL and thus reduced in vitro oxidation. LDL apolipoprotein analysis and oxidizability determination showed that this method is better than the longer sequential-isolation procedure. Adding butylated hydroxytoluene (BHT) to plasma as an antioxidant unpredictably increased the LDL oxidation lag time, making BHT unsuitable as an antioxidant. Adding EDTA appeared to be sufficient to prevent in vitro oxidation. Additionally, the diene production correlated highly with the concentration of thiobarbituric acid-reactive substances (r = 0.97). No relation between the vitamin E content of LDL and the oxidation lag time was found.

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