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 Identification of a Novel Apolipoprotein, ApoN, in Ovarian Follicular Fluid

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5231-5242 ◽  
Author(s):  
Moira K. O’Bryan ◽  
Lynda M. Foulds ◽  
James F. Cannon ◽  
Wendy R. Winnall ◽  
Julie A. Muir ◽  
...  
Keyword(s):  
Amino Acid ◽  
High Density Lipoprotein ◽  
Follicular Fluid ◽  
Low Density Lipoprotein ◽  
Regulatory Protein ◽  
Amino Acid Level ◽  
Density Lipoprotein ◽  
High Density ◽  
Significant Homology ◽  
Ovarian Follicular Fluid

Abstract A novel apolipoprotein, designated ApoN, has been identified in bovine ovarian follicular fluid using chromatographic purification methods, amino acid sequence analysis, molecular biology, and bioinformatics. The apolipoprotein is a hydrophobic 12-kDa protein processed from the C terminus of a 29-kDa precursor expressed in a number of tissues, including the ovary, testis, the anterior chamber of the eye, skeletal muscle, uterus, and liver. Bovine, porcine, and murine ApoN display significant homology at the amino acid level across the entire precursor sequence. Surprisingly, there appears to be no orthologous protein in the human, although an APON-like pseudogene is found on chromosome 12. The N-terminal fragment of the ApoN precursor shows significant homology with the N-terminal sequence of the precursor of the cholesterol transport regulatory protein ApoF, but the corresponding C-terminal sequences of ApoN and ApoF possess no homology. ApoN is present in the high-density lipoprotein fraction of bovine serum and both the high-density lipoprotein and low-density lipoprotein fractions of bovine follicular fluid and is found in several tissues that are associated with local immunological privilege. These data suggest that ApoN may play a role in steroidogenesis and/or immunoregulation in the gonads of nonhuman species, as well as similar roles in other tissues.

Abstract 12156: Greater Regression of Coronary Atherosclerosis With the Pre-Beta High-Density Lipoprotein Mimetic CER-001 in Patients With More Extensive Plaque Burden

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yu Kataoka ◽  
Jordan Andrews ◽  
MyNgan Duong ◽  
Tracy Nguyen ◽  
Nisha Schwarz ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density ◽  
Plaque Burden ◽  
Operating Characteristics ◽  
Chi Square ◽  
Coronary Syndrome ◽  
Imaging Characteristics ◽  
Atheroma Volume ◽  
Plaque Regression

Introduction: Infusing high-density lipoprotein (HDL) has been shown to promote plaque regression in patients with acute coronary syndrome (ACS). The factors associated with a greater propensity to regression have not been elucidated. We hypothesized greater plaque regression with HDL infusion would be observed in patients with greater baseline plaque burden. Methods: The CHI-SQUARE study compared the effect of infusing the pre-beta HDL mimetic CER-001 (3 to 12 mg/kg) versus placebo weekly for 5 weeks in patients with a recent ACS on plaque burden using serial intravascular ultrasound. Receiver operating characteristics curve analysis determined that a baseline percent atheroma volume (PAV) ≥30% optimally associated with greater regression. Clinical and imaging characteristics were compared in patients with baseline PAV <30% (n=74) or ≥30% (n=271). Results: There were no differences between the groups apart from greater use of statin in patients with baseline PAV ≥30% (100 v. 90%, p=0.01). Patients with a greater baseline PAV were more likely to demonstrate echolucency (20 v. 9%, p=0.02) and ultrasound attenuation (21 v. 7%, p=0.01), consistent with lipidic and inflammatory material. On serial evaluation, PAV decreased with CER-001 infusion in patients with baseline PAV ≥30% by -0.27% (p=0.01 v. baseline), but not in those with baseline PAV <30% (+0.43%, p=0.15 v. baseline, p=0.01 between plaque burden groups). The greatest PAV regression was observed with infusing CER-001 3 mg/kg in patients with baseline PAV ≥30% by 0.96% (p=0.04 v. baseline, p=0.02 v. placebo) (Table), but not in those patients with baseline PAV <30% (+0.08%, p=0.55 v. baseline, p=0.004 for comparison between plaque burden groups). Conclusions: Greater plaque regression with CER-001 3 mg/kg was observed in ACS patients with greater atheroma burden and more vulnerable features. The findings identify ACS patients with high-risk plaque features most likely to benefit from HDL mimetic therapy.

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 HDL (High-Density Lipoprotein) Remodeling and Magnetic Resonance Imaging–Assessed Atherosclerotic Plaque Burden

2020 ◽  
Vol 40 (10) ◽  
pp. 2481-2493 ◽  
Author(s):  
Soumaya Ben-Aicha ◽  
Laura Casaní ◽  
Natàlia Muñoz-García ◽  
Oriol Joan-Babot ◽  
Esther Peña ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
High Density Lipoprotein ◽  
Atherosclerotic Plaque ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
High Density ◽  
Plaque Burden ◽  
Resonance Imaging ◽  
Atherosclerotic Lesions

Objective: HDL (high-density lipoprotein) role in atherosclerosis is controversial. Clinical trials with CETP (cholesterylester transfer protein)-inhibitors have not provided benefit. We have shown that HDL remodeling in hypercholesterolemia reduces HDL cardioprotective potential. We aimed to assess whether hypercholesterolemia affects HDL-induced atherosclerotic plaque regression. Approach and Results: Atherosclerosis was induced in New Zealand White rabbits for 3-months by combining a high-fat-diet and double-balloon aortic denudation. Then, animals underwent magnetic resonance imaging (basal plaque) and randomized to receive 4 IV infusions (1 infusion/wk) of HDL isolated from normocholesterolemic (NC-HDL; 75 mg/kg; n=10), hypercholesterolemic (HC-HDL; 75 mg/Kg; n=10), or vehicle (n=10) rabbits. Then, animals underwent a second magnetic resonance imaging (end plaque). Blood, aorta, and liver samples were obtained for analyses. Follow-up magnetic resonance imaging revealed that NC-HDL administration regressed atherosclerotic lesions by 4.3%, whereas, conversely, the administration of HC-HDLs induced a further 6.5% progression ( P <0.05 versus basal). Plaque characterization showed that HC-HDL administered animals had a 2-fold higher lipid and cholesterol content versus those infused NC-HDL and vehicle ( P <0.05). No differences were observed among groups in CD31 levels, nor in infiltrated macrophages or smooth muscle cells. Plaques from HC-HDL administered animals exhibited higher Casp3 (caspase 3) content ( P <0.05 versus vehicle and NC-HDL) whereas plaques from NC-HDL infused animals showed lower expression of Casp3, Cox1 (cyclooxygenase 1), inducible nitric oxide synthase, and MMP (metalloproteinase) activity ( P <0.05 versus HC-HDL and vehicle). HDLs isolated from animals administered HC-HDL displayed lower antioxidant potential and cholesterol efflux capacity as compared with HDLs isolated from NC-HDL-infused animal and vehicle or donor HDL ( P <0.05). There were no differences in HDL-ApoA1 content, ABCA1 (ATP-binding cassette transporter A1) vascular expression, and SRB1 (scavenger receptor B1) and ABCA1 liver expression. Conclusions: HDL particles isolated from a hypercholesterolemic milieu lose their ability to regress and stabilize atherosclerotic lesions. Our data suggest that HDL remodeling in patients with co-morbidities may lead to the loss of HDL atheroprotective functions.

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.

Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency

2000 ◽  
Vol 11 (2) ◽  
pp. 117-122 ◽  
Author(s):  
Michael R. Hayden ◽  
Susanne M. Clee ◽  
Angela Brooks-Wilson ◽  
Jacques Genest ◽  
Alan Attie ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Regulatory Protein ◽  
Density Lipoprotein ◽  
High Density ◽  
Tangier Disease
Sign in / Sign up

Export Citation Format

Share Document