The role of lipid second messengers in aldosterone synthesis and secretion

Abstract

Second messengers are small rapidly diffusing molecules or ions that relay signals between receptors and effector proteins to produce a physiological effect. Lipid messengers constitute one of the four major classes of second messengers. The hydrolysis of two main classes of lipids, glycerophospholipids and sphingolipids, generate parallel profiles of lipid second messengers: phosphatidic acid (PA), diacylglycerol (DAG), and lysophosphatidic acid versus ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate, respectively. In this review, we examine the mechanisms by which these lipid second messengers modulate aldosterone production at multiple levels. Aldosterone is a mineralocorticoid hormone responsible for maintaining fluid volume, electrolyte balance, and blood pressure homeostasis. Primary aldosteronism is a frequent endocrine cause of secondary hypertension. A thorough understanding of the signaling events regulating aldosterone biosynthesis may lead to the identification of novel therapeutic targets. The cumulative evidence in this literature emphasizes the critical roles of PA, DAG, and sphingolipid metabolites in aldosterone synthesis and secretion. However, it also highlights the gaps in our knowledge, such as the preference for phospholipase D-generated PA or DAG, as well as the need for further investigation to elucidate the precise mechanisms by which these lipid second messengers regulate optimal aldosterone production.

Keywords: adrenal cortex; glycerophospholipids; intracellular signaling; phospholipases; primary aldosteronism; signal transduction; sphingolipids; steroidogenesis.

Fig. 1

Aldosterone biosynthesis. This schematic illustrates the enzymatic process through which aldosterone is synthesized in the mitochondria and endoplasmic reticulum of zona glomerulosa cells in the adrenal cortex. The cholesterol precursor can be derived from a combination of sources: mobilization of cholesteryl esters stored in lipid droplets by cholesteryl ester hydrolase, de novo synthesis in the endoplasmic reticulum, and receptor-mediated uptake and internalization of plasma lipoprotein-derived cholesterol. The free cholesterol is transported by the steroidogenic acute regulatory (StAR) protein from the outer to the inner mitochondrial membrane, which is the early rate-limiting step in steroidogenesis. In the inner mitochondrial membrane, steroidogenesis is initiated by the side-chain cleavage of cholesterol catalyzed by CYP11A1 to yield the steroid precursor, pregnenolone. Pregnenolone passively diffuses to the endoplasmic reticulum where it is converted to progesterone by type II 3β-hydroxysteroid dehydrogenase (3βHSD2). Progesterone is then hydroxylated to 11-deoxycorticosterone by CYP17. The final late rate-limiting steps of aldosterone biosynthesis are completed in the mitochondria, where aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to corticosterone and subsequently to aldosterone.

Fig. 2

Lipid-derived second messengers. Hydrolysis of two classes of lipids, glycerophospholipids and sphingolipids, generates parallel series of lipid second messengers. A: Hydrolysis of glycerophospholipids yields diacylglycerol (and inositol 1,4,5-trisphosphate), phosphatidic acid, and lysophosphatidic acid (and free fatty acids such as arachidonic acid). B: Hydrolysis of sphingolipids results in the production of ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate.

Fig. 3

Phosphoinositide signaling system. Binding of agonists to G protein-coupled receptors (GPCRs) promotes the exchange of GTP for GDP on Gα subunits, which then bind and activate phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) to generate two second messengers, inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ binds to IP₃ receptors on the endoplasmic reticulum (ER) causing the release of calcium into the cytosol. The elevated cytosolic calcium levels can bind to and activate calcium/calmodulin-dependent protein kinase (CaMK), calpains, and classical (in conjunction with calcium) protein kinase C (PKC) isoenzymes. DAG remains in the membrane and activates proteins such as novel PKC isoenzymes and protein kinase D (PKD) isoenzymes. Figure adapted from “Activation of Protein Kinase C (PKC)”, created with BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.

Fig. 4

Downstream effectors of phospholipase D-generated lipid second messengers. Phospholipase D (PLD) hydrolyzes phosphatidylcholine to produce choline and phosphatidic acid (PA). PA can interact and modulate the activity of various downstream effectors such as the kinase suppressor of Ras (KSR), mammalian target of rapamycin (mTOR), phosphatidylinositol 4-phosphate 5-kinase (PI4P5K), phosphodiesterase 4D3 (PDE4D3), protein serine/threonine phosphatase 1 (PP1), the small GTP-binding proteins Rac and c-Raf, ribosomal S6 kinase (RSK), son of sevenless (SOS), Src homology region 2 domain-containing phosphatase-1 (SHP1), and nuclear hormone receptor steroidogenic factor-1 (SF-1). PA can be dephosphorylated by lipid phosphate phosphatases (LPPs) to yield diacylglycerol (DAG). DAG effectors include the classical and novel protein kinase C (PKC) isoenzymes, protein kinase D (PKD) family of protein kinases, the Ras guanine nucleotide release proteins (RasGRP), the Rac GTPase-activating proteins chimaerins, and UNC13 proteins.