scholarly journals Activated Alpha-2 Macroglobulin Improves Insulin Response via LRP1 in Lipid-Loaded HL-1 Cardiomyocytes

2021 ◽  
Vol 22 (13) ◽  
pp. 6915
Author(s):  
Virginia Actis Dato ◽  
Gustavo Alberto Chiabrando
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Insulin Response ◽  
Density Lipoprotein ◽  
Low Density ◽  
Cardiac Damage ◽  
Therapeutic Implications ◽  
Glut4 Expression

Activated alpha-2 Macroglobulin (α2M*) is specifically recognized by the cluster I/II of LRP1 (Low-density lipoprotein Receptor-related Protein-1). LRP1 is a scaffold protein for insulin receptor involved in the insulin-induced glucose transporter type 4 (GLUT4) translocation to plasma membrane and glucose uptake in different types of cells. Moreover, the cluster II of LRP1 plays a critical role in the internalization of atherogenic lipoproteins, such as aggregated Low-density Lipoproteins (aggLDL), promoting intracellular cholesteryl ester (CE) accumulation mainly in arterial intima and myocardium. The aggLDL uptake by LRP1 impairs GLUT4 traffic and the insulin response in cardiomyocytes. However, the link between CE accumulation, insulin action, and cardiac dysfunction are largely unknown. Here, we found that α2M* increased GLUT4 expression on cell surface by Rab4, Rab8A, and Rab10-mediated recycling through PI3K/Akt and MAPK/ERK signaling activation. Moreover, α2M* enhanced the insulin response increasing insulin-induced glucose uptake rate in the myocardium under normal conditions. On the other hand, α2M* blocked the intracellular CE accumulation, improved the insulin response and reduced cardiac damage in HL-1 cardiomyocytes exposed to aggLDL. In conclusion, α2M* by its agonist action on LRP1, counteracts the deleterious effects of aggLDL in cardiomyocytes, which may have therapeutic implications in cardiovascular diseases associated with hypercholesterolemia.

scholarly journals Low density lipoprotein cholesterol and all-cause mortality rate: findings from a study on Japanese community-dwelling persons

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ryuichi Kawamoto ◽  
Asuka Kikuchi ◽  
Taichi Akase ◽  
Daisuke Ninomiya ◽  
Teru Kumagi
Keyword(s):  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Community Dwelling ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Adjusted Relative Risk ◽  
Low Density Lipoprotein Cholesterol ◽  
All Cause Mortality

Abstract Background Low-density lipoprotein cholesterol (LDL-C) independently impacts aging-related health outcomes and plays a critical role in cardiovascular diseases (CVDs). However, there are limited predictive data on all-cause mortality, especially for the Japanese community population. In this study, it was examined whether LDL-C is related to survival prognosis based on 7 or 10 years of follow-up. Methods Participants included 1610 men (63 ± 14 years old) and 2074 women (65 ± 12 years old) who participated in the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort) and who continued throughout the follow-up periods (follow-up rates: 94.8 and 98.0%). Adjusted relative risk estimates were obtained for all-cause mortality using a basic resident register. The data were analyzed by a Cox regression with the time variable defined as the length between the age at the time of recruitment and that at the end of the study (the age of death or censoring), and risk factors including gender, age, body mass index (BMI), presence of diabetes, lipid levels, renal function, serum uric acid levels, blood pressure, and history of smoking, drinking, and CVD. Results Of the 3684 participants, 326 (8.8%) were confirmed to be deceased. Of these, 180 were men (11.2% of all men) and 146 were women (7.0% of all women). Lower LDL-C levels, gender (male), older age, BMI under 18.5 kg/m2, and the presence of diabetes were significant predictors for all-cause mortality. Compared with individuals with LDL-C levels of 144 mg/dL or higher, the multivariable-adjusted Hazard ratio (and 95% confidence interval) for all-cause mortality was 2.54 (1.58–4.07) for those with LDL-C levels below 70 mg/dL, 1.71 (1.15–2.54) for those with LDL-C levels between 70 mg/dL and 92 mg/dL, and 1.21 (0.87–1.68) for those with LDL-C levels between 93 mg/dL and 143 mg/dL. This association was particularly significant among participants who were male (P for interaction = 0.039) and had CKD (P for interaction = 0.015). Conclusions There is an inverse relationship between LDL-C levels and the risk of all-cause mortality, and this association is statistically significant.

scholarly journals Silencing the Very Low-density Lipoprotein Receptor (VLDLR) Prevents Obesity Associated with Excess Lipid Deposition (P21-040-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Thomas Fungwe ◽  
Samuel Besong ◽  
Tahar Hajri
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Lipid Deposition ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Cardiac Lipotoxicity

Abstract Objectives Obesity is associated with an insulin resistant state, characterized by abnormalities in lipid metabolism, a leading cause of morbidity and mortality in cardiovascular diseases (CVD). Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of apolipoprotein E triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity associated lipotoxicity is not well understood. Methods In the current study, lean WT, VLDLR-deficient (VLDLR−/−), genetically obese leptin-deficient (Lepob/ob), and leptin–VLDLR double-null (Lepob/ob/VLDLR−/−) mice were used to determine the impact of VLDLR deficiency on obesity-induced cardiac lipotoxicity. Results The results showed that insulin sensitivity and glucose uptake were reduced in the hearts of Lepob/ob mice, and at the same time, VLDLR expression was upregulated and associated with increased VLDL uptake resulting in excess lipid deposition. These changes were accompanied by upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in Lepob/ob mice reduced VLDL uptake and prevented excess lipid deposition. Moreover, VLDLR deficiency reduced superoxide overproduction and normalized glucose uptake. In isolated cardiomyocytes, VLDLR deficiency prevented VLDL-mediated induction of NOx activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. An important observation showed that Lepob/ob/VLDLR−/− mice compared to Lepob/ob mice, had significantly improved heart performance and energetic reserves. Conclusions These findings suggest that that when VLDLR is silenced (deficiency), lipid deposition is also reduced, preventing cardiac lipotoxicity in obesity. In addition, the effects may be linked to the role of VLDLR on VLDL uptake, which triggers a cascade of events leading to insulin resistance and superoxide overproduction. Funding Sources Institutional Support. Howard University, Washington DC 20059 Hackensack University Medical Center, NJ 07601

The role of electronegative low-density lipoprotein in cardiovascular diseases and its therapeutic implications

2017 ◽  
Vol 27 (4) ◽  
pp. 239-246 ◽  
Author(s):  
Sumeyya Akyol ◽  
Jonathan Lu ◽  
Omer Akyol ◽  
Fatih Akcay ◽  
Ferah Armutcu ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Therapeutic Implications

scholarly journals Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis

2005 ◽  
Vol 393 (1) ◽  
pp. 255-265 ◽  
Author(s):  
Jiawei Chen ◽  
Yong Liu ◽  
Hongmei Liu ◽  
Paul L. Hermonat ◽  
Jawahar L. Mehta
Keyword(s):  
Endothelial Cells ◽  
Core Promoter ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Binding Motif ◽  
Low Density ◽  
Ang Ii ◽  
Oxidized Low Density Lipoprotein ◽  
Promoter Activation

LOX-1, a receptor for ox-LDL (oxidized low-density lipoprotein), has recently been determined to play a critical role in the progression of atherosclerosis. LOX-1 expression (mRNA and protein) has been shown to be up-regulated by pro-atherogenic stimuli, such as ox-LDL and Ang II (angiotensin II). However, the molecular mechanisms of these up-regulations are unclear. In the present study, we explored LOX-1 transcriptional promoter activation in response to ox-LDL and Ang II. Under basal states, LOX-1 core promoter (LOX-1 −35/+36) was found to be sufficient for its basal activity in HCAECs (human coronary artery endothelial cells). More importantly, we found that ox-LDL (60 μg/ml for 24 h) induced LOX-1 promoter activity significantly and that a 105 bp fragment (between nt −1599 and −1494) was required for this activation. Within this 106 bp fragment, there is a potential binding motif for the transcription factor Oct-1 (octamer-1). By electrophoretic mobility-shift assay, we observed the activation of Oct-1 by ox-LDL. The critical role of Oct-1 in ox-LDL-induced LOX-1 promoter activation was further confirmed by mutagenesis assay. For comparison, we also examined LOX-1 promoter activation in response to Ang II (1 μmol/l for 24 h). Interestingly, another promoter region, between nt −2336 and −1990, was required for Ang II-induced LOX-1 promoter activation. In conclusion, the present study strongly suggests that ox-LDL, by activating Oct-1, induces LOX-1 promoter activation. Furthermore, this study suggests that while ox-LDL and Ang II both induce LOX-1 expression in HCAECs, the underlying mechanisms of promoter activation are different from each other.

Structural and biophysical insight into cholesteryl ester-transfer protein

2011 ◽  
Vol 39 (4) ◽  
pp. 1000-1005 ◽  
Author(s):  
Justin Hall ◽  
Xiayang Qiu
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Low Density ◽  
Potential Treatment ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Insight Into

CETP (cholesteryl ester-transfer protein) is essential for neutral lipid transfer between HDL (high-density lipoprotein) and LDL (low-density lipoprotein) and plays a critical role in the reverse cholesterol transfer pathway. In clinical trials, CETP inhibitors increase HDL levels and reduce LDL levels, and therefore may be used as a potential treatment for atherosclerosis. In this review, we cover the analysis of CETP structure and provide insights into CETP-mediated lipid transfer based on a collection of structural and biophysical data.

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