scholarly journals Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4317
Author(s):  
Kyung-Hyun Cho
Keyword(s):  
High Density Lipoprotein ◽  
Bound States ◽  
Density Lipoprotein ◽  
High Density ◽  
Molar Ratio ◽  
Dependent Manner ◽  
Functional Impairments ◽  
Amyloid Aβ ◽  
Co Addition ◽  
Hdl Metabolism

Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.

scholarly journals Synthetic High-Density Lipoprotein (sHDL) Inhibits Steroid Production in HAC15 Adrenal Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3122-3129 ◽  
Author(s):  
Matthew J. Taylor ◽  
Aalok R. Sanjanwala ◽  
Emily E. Morin ◽  
Elizabeth Rowland-Fisher ◽  
Kyle Anderson ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Coenzyme A ◽  
Culture Media ◽  
Regulatory Protein ◽  
Density Lipoprotein ◽  
High Density ◽  
Plaque Burden ◽  
Dependent Manner ◽  
Steroid Production ◽  
Coenzyme A Reductase

High density lipoprotein (HDL) transported cholesterol represents one of the sources of substrate for adrenal steroid production. Synthetic HDL (sHDL) particles represent a new therapeutic option to reduce atherosclerotic plaque burden by increasing cholesterol efflux from macrophage cells. The effects of the sHDL particles on steroidogenic cells have not been explored. sHDL, specifically ETC-642, was studied in HAC15 adrenocortical cells. Cells were treated with sHDL, forskolin, 22R-hydroxycholesterol, or pregnenolone. Experiments included time and concentration response curves, followed by steroid assay. Quantitative real-time RT-PCR was used to study mRNA of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, lanosterol 14-α-methylase, cholesterol side-chain cleavage enzyme, and steroid acute regulatory protein. Cholesterol assay was performed using cell culture media and cell lipid extracts from a dose response experiment. sHDL significantly inhibited production of cortisol. Inhibition occurred in a concentration- and time-dependent manner and in a concentration range of 3μM–50μM. Forskolin (10μM) stimulated cortisol production was also inhibited. Incubation with 22R-hydroxycholesterol (10μM) and pregnenolone (10μM) increased cortisol production, which was unaffected by sHDL treatment. sHDL increased transcript levels for the rate-limiting cholesterol biosynthetic enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. Extracellular cholesterol assayed in culture media showed a positive correlation with increasing concentration of sHDL, whereas intracellular cholesterol decreased after treatment with sHDL. The current study suggests that sHDL inhibits HAC15 adrenal cell steroid production by efflux of cholesterol, leading to an overall decrease in steroid production and an adaptive rise in adrenal cholesterol biosynthesis.

scholarly journals High-density lipoprotein protects cardiomyocytes against necrosis induced by oxygen and glucose deprivation through SR-B1, PI3K, and AKT1 and 2

2018 ◽  
Vol 475 (7) ◽  
pp. 1253-1265 ◽  
Author(s):  
Kristina K. Durham ◽  
Kevin M. Chathely ◽  
Bernardo L. Trigatti
Keyword(s):  
Cell Death ◽  
High Density Lipoprotein ◽  
Ischemia Reperfusion ◽  
Density Lipoprotein ◽  
Glucose Deprivation ◽  
High Density ◽  
Dependent Manner ◽  
Protective Effects ◽  
Oxygen And Glucose Deprivation ◽  
Ventricular Cardiomyocytes

The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD-induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1−/− mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes.

scholarly journals Effect of Thyroid Dysfunction on High-Density Lipoprotein Subfraction Metabolism: Roles of Hepatic Lipase and Cholesteryl Ester Transfer Protein1

1998 ◽  
Vol 83 (8) ◽  
pp. 2921-2924 ◽  
Author(s):  
K. C. B. Tan ◽  
S. W. M. Shiu ◽  
A. W. C. Kung.
Keyword(s):  
High Density Lipoprotein ◽  
Cholesteryl Ester ◽  
Lipoprotein Lipase ◽  
Thyroid Dysfunction ◽  
Hepatic Lipase ◽  
Density Lipoprotein ◽  
High Density ◽  
Free T4 ◽  
Hdl Metabolism ◽  
Hypothyroid Patients

abstract To investigate the effect of thyroid dysfunction on high-density lipoprotein (HDL) metabolism, we measured HDL subfractions, apolipoprotein A-I containing particles (LpA-I and LpA-I:A-II), and the activities of enzymes involved in the remodeling and metabolism of HDL[ namely hepatic lipase (HL), lipoprotein lipase, and cholesteryl ester transfer protein (CETP)] in 18 hyperthyroid and 17 hypothyroid patients before and after treatment. HDL was subfractionated by density gradient ultracentrifugation, and LpA-I was analyzed by electroimmunodiffusion. The major changes were found in the HDL2 subfraction and in LpA-I particles. HDL2-C and LpA-I were reduced in hyperthyroidism (P < 0.01, P < 0.05, respectively) and increased in hypothyroidism (both P < 0.05) compared with their respective euthyroid matched controls. Changes in HDL2-cholesterol were reversed after treatment in both hyper- and hypothyroid patients, and LpA-I also decreased in the hypothyroid patients after treatment. HL (P < 0.05) and CETP activities (P < 0.05) were elevated in hyperthyroidism and reduced in hypothyroidism (P < 0.05, P < 0.01 respectively) and both were related to free T4 levels. The changes in HDL2-C and LpA-I correlated significantly with changes in HL after treatment but not with CETP or lipoprotein lipase. In summary, HDL metabolism was altered in thyroid dysfunction, and the effect of thyroid hormone on HDL was mediated mainly via its effect on HL activity.

scholarly journals High-density lipoprotein (HDL) metabolism and bone mass

2017 ◽  
Vol 233 (2) ◽  
pp. R95-R107 ◽  
Author(s):  
Nicholaos I Papachristou ◽  
Harry C Blair ◽  
Kyriakos E Kypreos ◽  
Dionysios J Papachristou
Keyword(s):  
Bone Mass ◽  
High Density Lipoprotein ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Osteoblastic Differentiation ◽  
High Density ◽  
Inflammatory Microenvironment ◽  
Marrow Adiposity ◽  
And Function ◽  
Hdl Metabolism

It is well appreciated that high-density lipoprotein (HDL) and bone physiology and pathology are tightly linked. Studies, primarily in mouse models, have shown that dysfunctional and/or disturbed HDL can affect bone mass through many different ways. Specifically, reduced HDL levels have been associated with the development of an inflammatory microenvironment that affects the differentiation and function of osteoblasts. In addition, perturbation in metabolic pathways of HDL favors adipoblastic differentiation and restrains osteoblastic differentiation through, among others, the modification of specific bone-related chemokines and signaling cascades. Increased bone marrow adiposity also deteriorates bone osteoblastic function and thus bone synthesis, leading to reduced bone mass. In this review, we present the current knowledge and the future directions with regard to the HDL–bone mass connection. Unraveling the molecular phenomena that underline this connection will promote the deeper understanding of the pathophysiology of bone-related pathologies, such as osteoporosis or bone metastasis, and pave the way toward the development of novel and more effective therapies against these conditions.

scholarly journals Aldosterone Production in Human Adrenocortical Cells Is Stimulated by High-Density Lipoprotein 2 (HDL2) through Increased Expression of Aldosterone Synthase (CYP11B2)

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 751-763 ◽  
Author(s):  
Yewei Xing ◽  
Anthony Cohen ◽  
George Rothblat ◽  
Sandhya Sankaranarayanan ◽  
Ginny Weibel ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Kinase Inhibitor ◽  
Cell Model ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
High Density ◽  
Dependent Manner ◽  
Active Components ◽  
Calmodulin Kinase ◽  
Aldosterone Production

Adrenal aldosterone production is regulated by physiological agonists at the level of early and late rate-limiting steps. Numerous studies have focused on the role of lipoproteins including high-density lipoprotein (HDL) as cholesterol providers in this process; however, recent research suggests that HDL can also act as a signaling molecule. Herein, we used the human H295R adrenocortical cell model to study the effects of HDL on adrenal aldosterone production and CYP11B2 expression. HDL, especially HDL2, stimulated aldosterone synthesis by increasing expression of CYP11B2. HDL treatment increased CYP11B2 mRNA in both a concentration- and time-dependent manner, with a maximal 19-fold increase (24 h, 250 μg/ml of HDL). Effects of HDL on CYP11B2 were not additive with natural agonists including angiotensin II or K+. HDL effects were likely mediated by a calcium signaling cascade, because a calcium channel blocker and a calmodulin kinase inhibitor abolished the CYP11B2-stimulating effects. Of the two subfractions of HDL, HDL2 was more potent than HDL3 in stimulating aldosterone and CYP11B2. Further studies are needed to identify the active components of HDL, which regulate aldosterone production.

scholarly journals The Late-Gestational Triglyceride to High-Density Lipoprotein Cholesterol Ratio Is Associated with Neonatal Macrosomia in Women without Diabetes Mellitus

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Mengru Yu ◽  
Wenting Wang ◽  
Hong Wang
Keyword(s):  
Body Weight ◽  
High Density Lipoprotein ◽  
Pregnant Women ◽  
High Density Lipoprotein Cholesterol ◽  
Density Lipoprotein ◽  
Maternal Serum ◽  
High Density ◽  
Lipoprotein Cholesterol ◽  
Maternal Body Mass Index ◽  
Dependent Manner

Objective. To investigate the associations between late-gestational dyslipidemia, expressed as the ratio between triglycerides (TGs) and high-density lipoprotein cholesterol (HDL), and the risk of macrosomia among nondiabetic pregnant women. Methods. In this case-control study, 171 pregnant women who delivered macrosomia newborns were recruited from a total of 1856 nondiabetic pregnant women who delivered a singleton, nonanomalous newborn. A total of 684 normal controls were one-to-four matched by age. Logistic regression analysis was used to analyze the association between the TG/HDL ratio and the neonatal body weight as well as the risk of macrosomia. Results. The maternal serum TG and TG/HDL levels were much higher in the macrosomia group, while the maternal serum HDL-C levels were much lower in the macrosomia group than those in the control group. However, the serum total cholesterol (TC) and LDL-C levels were not significantly different between the two groups. Furthermore, maternal TG/HDL levels were positively associated with neonatal body weight. The confounding factors including maternal age, maternal height, gestational age, maternal body mass index (BMI), FPG, SBP, and neonatal sex were adjusted. A positive association between TG/HDL and neonatal body weight was still found. Moreover, the prevalence of macrosomia increased markedly in a dose-dependent manner as with maternal TG/HDL levels increased. Conclusions. Maternal serum TG/HDL levels at late gestation are positively associated with neonatal body weight and the risk of macrosomia in women without DM. Maintaining maternal lipid levels in an appropriate range is important in the context of fetal overgrowth and primary prevention of macrosomia.

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