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 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 Acute effects of ethanol on the perfused rat liver. Studies on lipid and carbohydrate metabolism, substrate cycling and perfusate amino acids

1979 ◽  
Vol 184 (1) ◽  
pp. 97-106 ◽  
Author(s):  
David L. Topping ◽  
Dallas G. Clark ◽  
Gerald B. Storer ◽  
Rodney P. Trimble ◽  
Richard J. Illman
Keyword(s):  
Amino Acids ◽  
Carbohydrate Metabolism ◽  
Ketone Bodies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fold Increase ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Ethanol Infusion ◽  
Glucose Output

1. Livers from fed rats were perfused in situ with whole rat blood containing glucose labelled uniformly with 14C and specifically with 3H at positions 2, 3 or 6. 2. When ethanol was infused at a concentration of 24μmol/ml of blood the rate of utilization was 2.8μmol/min per g of liver. 3. Ethanol infusion raised perfusate glucose concentrations and caused a 2.5-fold increase in hepatic glucose output. 4. Final blood lactate concentrations were decreased in ethanol-infused livers, but the mean uptake of lactate from erythrocyte glycolysis was unaffected. 5. Production of ketone bodies (3‐hydroxybutyrate+3‐oxobutyrate) and the ratio [3‐hydroxybutyrate]/[3‐oxobutyrate] were raised by ethanol. 6. Formation of 3H2O from specifically 3H-labelled glucoses increased in the order [6-3H]<[3-3H]<[2-3H]. Production of 3H2O from [2-3H]glucose was significantly greater than that from [3-3H]glucose in both control and ethanol-infused livers. Ethanol significantly decreased 3H2O formation from all [3H]glucoses. 7. Liver glycogen content was unaffected by ethanol infusion. 8. Production of very-low-density lipoprotein triacylglycerols was inhibited by ethanol and there was a small increase in liver triacylglycerols. Very-low-density-lipoprotein secretion was negatively correlated with the ratio [3‐hydroxybutyrate]/[3‐oxobutyrate]. Perfusate fatty acid concentrations and molar composition were unaffected by perfusion with ethanol. 9. Ethanol decreased the incorporation of [U-14C]glucose into fatty acids and cholesterol. 10. The concentration of total plasma amino acids was unchanged by ethanol, but the concentrations of alanine and glycine were decreased and ([glutamate]+[glutamine]) was raised. 11. It is proposed that the observed effects of ethanol on carbohydrate metabolism are due to an increased conversion of lactate into glucose, possibly by inhibition of pyruvate dehydrogenase. The increase in gluconeogenesis is accompanied by diminished substrate cycling at glucose–glucose 6-phosphate and at fructose 6-phosphate–fructose 1,6-bisphosphate.

Abstract 15187: Very Low-density Lipoprotein Signals Through Sphingosine-1-phosphate Receptors Upon Binding to Scavenger Receptor Class B, Type I in Human Adrenocortical Cells

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shinjini Chowdhury ◽  
Vivek Choudhary ◽  
Mrunal Choudhary ◽  
Wendy B Bollag
Keyword(s):  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Type I ◽  
Low Density ◽  
Adrenocortical Cells ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Aldosterone Production ◽  
Sphingosine 1 Phosphate

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of both very low-density lipoprotein (VLDL) and sphingosine-1-phosphate (S1P). VLDL has been shown to stimulate aldosterone production in multiple zona glomerulosa cell models. S1P is transported in blood bound to lipoproteins such as VLDL, low-density lipoprotein, and high-density lipoprotein (HDL); the VLDL particle contains the highest levels of S1P. S1P in HDL has been shown to promote interactions between scavenger receptor class B, type I (SR-BI) and S1P receptor 1 (S1PR1). We hypothesized that like HDL, VLDL will signal through S1PRs upon binding to SR-BI; therefore, VLDL-induced aldosterone production will be inhibited by S1PR antagonists. Human adrenocortical cells (HAC15) were treated with VLDL and/or an S1PR1 antagonist (Ex26) for 24 h. The expression of steroidogenic genes and aldosterone production were monitored by qRT-PCR and radioimmunoassay, respectively. Ex26 inhibited VLDL-induced increases in CYP11B2 (22-fold) and StAR (1.5-fold) expression by 43% and 10%, respectively. Ex26 had no effect on VLDL-stimulated increase in NR4A1 expression. In addition, the VLDL-induced 5-fold increase in aldosterone levels was significantly inhibited by Ex26 (36%). Our results indicate that like HDL, VLDL likely signals by binding to SR-BI and activating S1PR1, such that an S1PR1 antagonist reduces VLDL-induced aldosterone production. Further investigation into these steroidogenic signaling pathways is warranted and may lead to the identification of therapeutic targets such as S1PR1 to potentially treat obesity-associated hypertension.

scholarly journals The farnesoid X receptor induces very low density lipoprotein receptor gene expression

FEBS Letters ◽  
2004 ◽  
Vol 566 (1-3) ◽  
pp. 173-177 ◽  
Author(s):  
Audrey Sirvent ◽  
Thierry Claudel ◽  
Geneviève Martin ◽  
John Brozek ◽  
Vladimir Kosykh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Farnesoid X Receptor ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Receptor Gene Expression
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