Journal of Endocrinology

The VLDL-activated pathway to aldosterone production in the zona glomerulosa. (A) Shown are the early effects of VLDL that promote acute aldosterone secretion. (1) Very low-density lipoprotein (VLDL) apparently binds to the scavenger receptor, class B, type 1 (SR-B1) and (2) activates, through an unknown mechanism, a phosphoinositide-specific phospholipase C (PI-PLC) that cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) to yield inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). Various signaling cascades are then initiated simultaneously. For example, IP₃ binds to IP₃ receptors (IP₃R) on the endoplasmic reticulum to release the stored calcium and increase cytosolic calcium levels (occurring within a few minutes of VLDL exposure); the increased cytosolic calcium levels activate calcium/calmodulin-dependent protein kinase (CaMK). At the same time, the other signal formed within minutes is DAG; DAG activates protein kinase C (PKC) isoforms to stimulate the activity of extracellular signal-regulated kinase (ERK), again within minutes of VLDL treatment. VLDL-stimulated ERK, like the angiotensin II (AngII)-activated enzyme, may, in turn, phosphorylate and activate cholesterol ester hydrolase (Cherradi et al. 2003), also known as hormone-sensitive lipase, to release cholesterol esters stored in lipid droplets. ERK also likely phosphorylates StAR, thereby enhancing its cholesterol transport activity (Poderoso et al. 2008). In addition, within minutes of VLDL exposure, activated PKC induces phosphorylation and activation of members of the activating transcription factor/cAMP response element binding protein family of transcription factors (ATF/CREB) to increase after a few hours the levels of steroidogenic acute regulatory protein (StAR). StAR allows transport of cholesterol into the inner mitochondrial membrane where it can be acted upon by the cholesterol side-chain cleavage complex (CYP11A1) located there to initiate steroidogenesis. (B) The initial (1) binding of VLDL to SRB1 and (2) activation of PI-PLC also activates phospholipase D (PLD) (within an hour, the earliest time tested) via an unknown mechanism. PLD catalyzes phosphatidylcholine hydrolysis to yield phosphatidic acid (PA), which can be dephosphorylated to DAG (by lipins) to sustain PKC activation and aldosterone production. PA may also have its own effector enzymes, such as Raf-1, a protein kinase upstream of ERK, as reviewed in Bollag (2014). PKC-elicited phosphorylation of ATF/CREB also induces the expression not only of StAR but also of aldosterone synthase, encoded by the gene CYP11B2, after 6–12 h. (By analogy to angiotensin II, CaMK also may induce the expression of members of this family (Felizola et al. 2014). CYP11B2 transcription is also promoted by the VLDL-induced increase in the mRNA and protein expression of the transcription factor Nurr1 (the protein levels of which are elevated after several hours of VLDL treatment). CYP11B2 in the mitochondria catalyzes the final steps in the production of aldosterone.