scholarly journals Phospholipase D Activity Underlies Very-Low-Density Lipoprotein (VLDL)-induced Aldosterone Production in Adrenal Glomerulosa Cells

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3550-3560 ◽  
Author(s):  
Ying-Ying Tsai ◽  
William E. Rainey ◽  
Zhi-qiang Pan ◽  
Michael A. Frohman ◽  
Vivek Choudhary ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Phospholipase D ◽  
Low Density Lipoprotein ◽  
Primary Cultures ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Peripheral Tissues ◽  
Aldosterone Production ◽  
Glomerulosa Cells

Abstract Aldosterone is the mineralocorticoid responsible for sodium retention, thus increased blood volume and pressure. Excessive production of aldosterone results in high blood pressure as well as renal disease, stroke, and visual loss via both direct effects and effects on blood pressure. Weight gain is often associated with increased blood pressure, but it remains unclear how obesity increases blood pressure. Obese patients typically have higher lipoprotein levels; moreover, some studies have suggested that aldosterone levels are also elevated and represent a link between obesity and hypertension. Very-low-density lipoprotein (VLDL) functions to transport triglycerides from the liver to peripheral tissues. Although previous studies have demonstrated that VLDL can stimulate aldosterone production, the mechanisms underlying this effect are largely unclear. Here we show for the first time that phospholipase D (PLD) is involved in VLDL-induced aldosterone production in both a human adrenocortical cell line (HAC15) and primary cultures of bovine zona glomerulosa cells. Our data also reveal that PLD mediates steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression via increasing the phosphorylation (activation) of their regulatory transcription factors. Finally, by using selective PLD inhibitors, our studies suggest that both PLD1 and PLD2 isoforms play an important role in VLDL-induced aldosterone production.

scholarly journals Very low-density lipoprotein (VLDL)-induced signals mediating aldosterone production

2017 ◽  
Vol 232 (2) ◽  
pp. R115-R129 ◽  
Author(s):  
Ying-Ying Tsai ◽  
William E Rainey ◽  
Wendy B Bollag
Keyword(s):  
Blood Pressure ◽  
Transcription Factors ◽  
Low Density Lipoprotein ◽  
Elevated Serum ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Peripheral Tissues ◽  
Fat Deposits ◽  
Aldosterone Production

Aldosterone, secreted by the adrenal zona glomerulosa, enhances sodium retention, thus increasing blood volume and pressure. Excessive production of aldosterone results in high blood pressure and contributes to cardiovascular and renal disease, stroke and visual loss. Hypertension is also associated with obesity, which is correlated with other serious health risks as well. Although weight gain is associated with increased blood pressure, the mechanism by which excess fat deposits increase blood pressure remains unclear. Several studies have suggested that aldosterone levels are elevated with obesity and may represent a link between obesity and hypertension. In addition to hypertension, obese patients typically have dyslipidemia, including elevated serum levels of very low-density lipoprotein (VLDL). VLDL, which functions to transport triglycerides from the liver to peripheral tissues, has been demonstrated to stimulate aldosterone production. Recent studies suggest that the signaling pathways activated by VLDL are similar to those utilized by AngII. Thus, VLDL increases cytosolic calcium levels and stimulates phospholipase D (PLD) activity to result in the induction of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression. These effects seem to be mediated by the ability of VLDL to increase the phosphorylation (activation) of their regulatory transcription factors, such as the cAMP response element-binding (CREB) protein family of transcription factors. Thus, research into the pathways by which VLDL stimulates aldosterone production may identify novel targets for the development of therapies for the treatment of hypertension, particularly those associated with obesity, and other aldosterone-modulated pathologies.

scholarly journals Chronic exogenous hyperinsulinaemia does not modify the acute inhibitory effect of insulin on the secretion of very-low-density lipoprotein triacylglycerol and apolipoprotein B in primary cultures of rat hepatocytes

1996 ◽  
Vol 314 (1) ◽  
pp. 103-108 ◽  
Author(s):  
Catherine S. BOURGEOIS ◽  
David WIGGINS ◽  
Geoffrey F. GIBBONS
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Primary Cultures ◽  
Density Lipoprotein ◽  
Inhibitory Effect ◽  
Cell Protein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Plasma Insulin Concentration

Male Wistar rats were fitted with subcutaneous osmotic minipumps that delivered insulin at a constant rate of 0.20 i.u./h for 7 days. This treatment raised the plasma insulin concentration from 31±4 to 201±64 μ-i.u./ml. Hepatocytes prepared from the hyperinsulinaemic animals secreted very-low-density lipoprotein (VLDL) triacylglycerol (TAG) at a higher rate (172±21 μg per 24 h per mg cell protein) than did those from sham-operated controls (109±12 μg per 24 h per mg) (P < 0.05). However, chronic exogenous hyperinsulinaemia had no stimulatory effect on the secretion of VLDL apolipoprotein B (apoB) in derived hepatocytes compared with those from the sham-operated controls (2.32±0.38 compared with 3.09±0.40 μg per 24 h per mg). Hepatocytes from the hyperinsulinaemic rats thus secreted larger VLDL particles as evidenced by the increased TAG:apoB ratio (78.4±13.1 compared with 38.4±7.6; P < 0.05). In hepatocytes from the hyperinsulinaemic rats a larger proportion of the newly synthesized TAG was secreted as VLDL. Hepatocytes from the hyperinsulinaemic and the sham-operated control animals were equally sensitive to the inhibitory effect of insulin added in vitro on the secretion of VLDL TAG. Insulin added in vitro to the culture medium of hepatocytes from hyperinsulinaemic animals significantly decreased the TAG:apoB ratio of the secreted VLDL. This change did not occur in hepatocytes from sham-operated rats. These results suggest that, in vivo, chronic hyperinsulinaemia is not in itself sufficient to desensitize the liver to the acute inhibitory effect of insulin on the secretion of VLDL.

scholarly journals The role of postprandial very-low-density lipoprotein in the development of atrial remodeling in metabolic syndrome

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Hsiang-Chun Lee ◽  
Shyi-Jang Shin ◽  
Jih-Kai Huang ◽  
Ming-Yen Lin ◽  
Yu-Hsun Lin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Waist Circumference ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atrial Remodeling ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Hip Circumference

Abstract Background Negatively charged very-low-density lipoprotein (VLDL-χ) in metabolic syndrome (MetS) patients exerts cytotoxic effects on endothelial cells and atrial myocytes. Atrial cardiomyopathy, manifested by atrial remodeling with a dilated diameter, contributes to atrial fibrillation pathogenesis and predicts atrial fibrillation development. The correlation of VLDL-χ with atrial remodeling is unknown. This study investigated the association between VLDL-χ and remodeling of left atrium. Methods Consecutively, 87 MetS and 80 non-MetS individuals between 23 and 74 years old (50.6% men) without overt cardiovascular diseases were included in the prospective cohort study. Blood samples were collected while fasting and postprandially (at 0.5, 1, 2, and 4 h after a unified meal). VLDL was isolated by ultracentrifugation; the percentile concentration of VLDL-χ (%) was determined by ultra-performance liquid chromatography. The correlations of left atrium diameter (LAD) with variables including VLDL-χ, LDL-C, HDL-C, triglycerides, glucose, and blood pressure, were analyzed by multiple linear regression models. A hierarchical linear model was conducted to test the independencies of each variable’s correlation with LAD. Results The mean LAD was 3.4 ± 0.5 cm in non-MetS subjects and 3.9 ± 0.5 cm in MetS patients (P < 0.01). None of the fasting lipid profiles were associated with LAD. VLDL-χ, BMI, waist circumference, hip circumference, and blood pressure were positively correlated with LAD (all P < 0.05) after adjustment for age and sex. Significant interactions between VLDL-χ and blood pressure, waist circumference, and hip circumference were observed. When adjusted for obesity- and blood pressure-related variables, 2-h postprandial VLDL-χ (mean 1.30 ± 0.61%) showed a positive correlation with LAD in MetS patients. Each 1% VLDL-χ increase was estimated to increase LAD by 0.23 cm. Conclusions Postprandial VLDL-χ is associated with atrial remodeling particularly in the MetS group. VLDL-χ is a novel biomarker and may be a therapeutic target for atrial cardiomyopathy in MetS patients. Trial registration ISRCTN 69295295. Retrospectively registered 9 June 2020.

scholarly journals Metabolic evaluation in overweight and obese cats and association with blood pressure

2017 ◽  
Vol 48 (1) ◽  
Author(s):  
Vanessa Danielle de Freitas ◽  
Alessandra Ramos Castilho ◽  
Luciana Auxiliadora Viebrantz da Conceição ◽  
Valéria Régia Franco Sousa ◽  
Adriane Jorge Mendonça ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Levels ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Metabolic Evaluation ◽  
Morphometric Measurements ◽  
Metabolic Alterations ◽  
Significant Difference

ABSTRACT: Obesity has been increasing in cats andis associated with metabolic and cardiovascular diseases. The association of these alterations can trigger the onset of metabolic syndrome (MS). Therefore, this study aimed to analyze the serum levels of glucose, fructosamine, cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein (VLDL), andalanine aminotransferase of cats and to identify the possibility of MS,as well as to evaluate changes in arterial pressure. Thirty-seven cats were classified by ECC and morphometric measurements, namely, 15 obese, 12 overweight, and 10 controls. Nocat manifested MS. Only VLDL had a statistically significant difference (P<0.05) between groups. Therefore, obesity may not be associated with arterial hypertension, and more studies are needed to evaluate the metabolic alterations in overweight and obese cats.

scholarly journals Risk Factors for Polyvascular Involvement in Patients With Peripheral Artery Disease: A Mendelian Randomization Study

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Ozan Dikilitas ◽  
Benjamin A. Satterfield ◽  
Iftikhar J. Kullo
Keyword(s):  
Blood Pressure ◽  
Lipid Content ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Peripheral Artery ◽  
Artery Disease ◽  
Intermediate Density

Background Atherosclerosis in >1 vascular bed (ie, polyvascular disease), often a feature of peripheral artery disease (PAD), is associated with high morbidity and mortality. We sought to identify risk factors for polyvascular involvement in patients with PAD. Methods and Results We performed 2‐sample Mendelian randomization using an inverse‐variance‐weighted approach, to assess 60 exposures including size and lipid content of atherogenic lipoproteins, blood pressure, glycated hemoglobin, and smoking as causal mediators for polyvascular disease in patients with PAD. Genetic instruments for these exposures were obtained from prior genome‐wide association studies. Patients with PAD were from the Mayo Vascular Disease Biorepository, and polyvascular disease (ie, concomitant coronary heart disease, cerebrovascular disease, and/or abdominal aortic aneurysm) was ascertained by validated phenotyping algorithms. Of 3279 patients with PAD, 61% had polyvascular disease. Genetically predicted levels of the lipid content and/or particle measures of very small and small size very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein were associated with polyvascular disease: odds ratios (OR) of 1.80 (95% CI, 1.23–2.61), 1.70 (95% CI, 1.17–2.61), and 1.40 (95% CI, 1.09–1.80) per 1 SD increase in genetically determined levels, respectively. Both genetically predicted diastolic and systolic blood pressure were associated with polyvascular disease; OR per 10 mm Hg genetic increase in diastolic and systolic blood pressure were 1.66 (95% CI, 1.19–2.33) and 1.31 (95% CI, 1.07–1.60), respectively. Conclusions Lifetime exposure to increased lipid content and levels of very small and small very low‐density lipoprotein, intermediate‐density lipoprotein, and large low‐density lipoprotein particles as well as elevated blood pressure are associated with polyvascular involvement in patients with PAD. Reduction in levels of such exposures may limit progression of atherosclerosis in patients with PAD.

Abstract P250: Sphingosine-1-phosphate Receptor Agonist And Very Low-density Lipoprotein Regulate Aldosterone Production Via Lipin-1 In Human Adrenocortical Cells

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Shinjini Chowdhury ◽  
Vivek Choudhary ◽  
Mrunal Choudhary ◽  
Xunsheng Chen ◽  
Wendy B Bollag
Keyword(s):  
Gene Expression ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Lipid Signal ◽  
Aldosterone Production ◽  
Sphingosine 1 Phosphate ◽  
Lipin 1

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of both sphingosine-1-phosphate (S1P) and very low-density lipoprotein (VLDL). S1P has been reported to be a novel stimulator of aldosterone secretion and phospholipase D (PLD) activity. VLDL has also been shown to stimulate aldosterone production in multiple zona glomerulosa cell models via PLD. PLD is an enzyme that hydrolyzes phosphatidylcholine to phosphatidic acid (PA) which can then be converted to diacylglycerol (DAG) by lipin-1. However, it is unclear which of the two lipid signals, PA or DAG, underlies PLD’s mediation of aldosterone production. We hypothesized that the S1P1 receptor (S1PR1) agonist, SEW2871, (and VLDL) induces steroidogenesis and therefore aldosterone production via lipin-1-mediated metabolism of PA to DAG, with our hypothesis focusing on DAG as the key lipid signal produced by PLD (indirectly). In HAC15 cells, lipin-1 was overexpressed using an adenovirus or inhibited using propranolol followed by treatment with or without SEW2871 (or VLDL) for 24 h. Steroidogenic gene expression and aldosterone levels were monitored by qRT-PCR and radioimmunoassay, respectively. We demonstrated that lipin-1 overexpression (OE) enhanced the SEW2871-stimulated 109-fold increase in CYP11B2 expression by 26% while lipin-1 inhibition decreased the SEW2871-stimulated 56-fold increase in CYP11B2 expression by 74%. While lipin-1 OE had no further effect, propranolol reduced SEW2871-stimulated increases in NR4A1 (2-fold) and NR4A2 (9-fold) mRNA levels by 22% and 52% respectively. The SEW2871-stimulated increase in aldosterone production was inhibited by propranolol (53%), although it was not enhanced by lipin-1 OE. Similar results were obtained with VLDL. Our results are, therefore, suggestive of DAG being the key lipid signal since regulating lipin-1 affects S1PR1 agonist- and VLDL-stimulated steroidogenic gene expression and ultimately, aldosterone production. Our study warrants further investigation into these steroidogenic signaling pathways which can lead to the identification of novel therapeutic targets such as lipin-1, or its downstream pathways, to potentially treat obesity-associated hypertension.

scholarly journals Extracellular fatty acids are not utilized directly for the synthesis of very-low-density lipoprotein in primary cultures of rat hepatocytes

1992 ◽  
Vol 287 (3) ◽  
pp. 749-753 ◽  
Author(s):  
G F Gibbons ◽  
S M Bartlett ◽  
C E Sparks ◽  
J D Sparks
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Acid Concentration ◽  
Low Density Lipoprotein ◽  
Primary Cultures ◽  
Density Lipoprotein ◽  
Fatty Acid Concentration ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Extracellular Fatty Acid

In hepatocytes cultured in the presence of oleate (initial concn. 0.75 mM), the secretion of very-low-density lipoprotein (VLDL) triacylglycerol and, to a lesser extent, apoprotein B (apoB) increased with time, whereas there was a large decline in the extracellular concentration of fatty acid. There was thus no synchronous relationship between the extracellular fatty acid concentration and the secretion of VLDL. Rather, the appearance of VLDL in the medium was dependent on the intracellular triacylglycerol concentration. At a given concentration of extracellular fatty acid, cells depleted of triacylglycerol secreted less VLDL triacylglycerol and apoB than did control cells. A similar pattern was observed for triacylglycerol newly synthesized from extracellular [3H]oleate. By contrast, the synthesis and output of ketone bodies were directly dependent on the fatty acid concentration of the medium. These results suggest that, at least for oleic acid, extracellular fatty acids are not utilized directly for VLDL assembly, but first enter a temporary intracellular storage pool of triacylglycerol, which is the immediate precursor of secreted triacylglycerol. The size of this pool then determines the rate of secretion of VLDL triacylglycerol apoB. Ketogenesis, on the other hand, relies mainly on the direct utilization of extracellular fatty acids.

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