Phospholipase D mediates very low-density lipoprotein-induced aldosterone production, in part, via lipin-1

in Journal of Molecular Endocrinology
Authors:
Shinjini C SpauldingDepartment of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA

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Vivek ChoudharyDepartment of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
Charlie Norwood VA Medical Center, Augusta, Georgia, USA

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Wendy B BollagDepartment of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
Charlie Norwood VA Medical Center, Augusta, Georgia, USA

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https://orcid.org/0000-0003-3146-162X
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Correspondence should be addressed to W B Bollag: wbollag@augusta.edu

Wendy Bollag is a Senior Editor on the JOE–JME joint editorial board. Wendy Bollag was not involved in the review or editorial process for this paper, on which she is listed as an author.

DOI:
https://doi.org/10.1530/JME-22-0196
Volume/Issue:
Volume 70: Issue 4
Article Type:
Research Article
Article ID:
e220196
Online Publication Date:
27 Mar 2023
Copyright:
© Society for Endocrinology 2023
Restricted access

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Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of very low-density lipoprotein (VLDL). VLDL has been shown to induce aldosterone production in multiple adrenal zona glomerulosa models, mediated in part by phospholipase D (PLD). PLD is an enzyme that hydrolyzes phosphatidylcholine to produce phosphatidic acid (PA), a lipid second messenger that can also be dephosphorylated by lipin to yield diacylglycerol (DAG), yet another lipid signal. However, it is unclear which of the two lipid second messengers, PA or DAG, underlies PLD’s mediation of aldosterone production. We hypothesized that the key signal produced by PLD (indirectly) is DAG such that PLD mediates VLDL-induced aldosterone production via lipin-mediated metabolism of PA to DAG. To assess the role of lipin in VLDL-induced aldosterone production, lipin-1 was overexpressed (using an adenovirus) or inhibited (using propranolol) in HAC15 cells followed by treatment with or without VLDL. Lipin-1 overexpression enhanced the VLDL-stimulated increase in CYP11B2 expression (by 75%), and lipin-1 inhibition decreased the VLDL-stimulated increase in CYP11B2 expression (by 66%). Similarly, the VLDL-stimulated increase in aldosterone production was enhanced by lipin-1 overexpression (182%) and was decreased by lipin inhibition (80%). Our results are suggestive of DAG being the key lipid signal since manipulating lipin-1 levels/activity affects VLDL-stimulated steroidogenic gene expression and ultimately, aldosterone production. Our study warrants further investigation into VLDL-stimulated steroidogenic signaling pathways which may lead to the identification of novel therapeutic targets, such as lipin-1 and its downstream pathways, to potentially treat obesity-associated hypertension.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2023
Article ID:
e220196
Article Type:
Research Article
Received Date:
11 Jan 2023
Accepted Date:
13 Feb 2023
Print Publication Date:
01 May 2023
Online Publication Date:
27 Mar 2023
Keywords:
aldosterone; adrenal steroidogenesis; lipin; very low-density lipoprotein

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