Lipid metabolism in the adrenal gland

Abstract

The adrenal gland consists of the medulla and the cortex. The chromaffin cells of the adrenal medulla release catecholamines via regulated exocytosis. Vesicle formation, trafficking, maturation and fusion with the plasma membrane are orchestrated by lipids such as cholesterol, diacylglycerol, phosphatidic acid and phosphatidylinositol-4,5-bisphosphate. On the other hand, the adrenal cortex is a highly specialized lipid-metabolizing organ secreting steroid hormones. Cholesterol, acquired from circulating lipoproteins and de novo biosynthesis, is mobilized from intracellular stores and transported to mitochondria to be used as a substrate for steroidogenesis. Steroidogenesis is regulated by free polyunsaturated fatty acids (PUFA) and an increased PUFA content in phospholipids promotes steroidogenesis. Cholesterol efflux and lipid-processing macrophages further contribute to lipid homeostasis in the adrenal gland. Given that lipidomics have revolutionized our perception of cell function, we anticipate that this will also hold true for the investigation of adrenocortical function. Such investigations may pinpoint novel targets for the management of abnormal adrenal function.

Keywords: adrenal cortex; adrenal medulla; aldosterone; cholesterol metabolism; cortisol; lipid metabolism; phospholipids.

Figure 1

Lipid metabolism in adrenocortical cells. In adrenocortical cells, cholesterol derives from circulating lipoproteins and de novo biosynthesis. Low-density lipoproteins (LDLs) are internalized via the LDL receptor (LDLR) and endocytosis, while high-density lipoproteins (HDL) are taken up via scavenger receptor class B type I (SCARB1) (39, 40). Excess cholesterol is either esterified by SOAT1 and stored in lipid droplets (57) or exported via Adenosine triphosphate (ATP)-binding cassette transporter G1 (ABCG1) (85). Adrenocorticotropic hormone (ACTH) binding to melanocortin 2 receptor (MC2R) activates protein kinase A (PKA), which induces hormone-sensitive lipase (HSL) phosphorylation and translocation to the lipid droplets, assisted by perilipin 2 (PLIN2), promoting cholesterol release (66, 67). Angiotensin II (Ang II) binds to the angiotensin type 1 receptor (AGT1R), triggering the increase of intracellular calcium levels, leading to activation of calmodulin kinase (CaMK), which induces StAR activation (29). De novo synthesis of cholesterol is regulated by the rate-limiting conversion of acetyl-CoA to mevalonate via hydroxymethylglutaryl-CoA (HMG-CoA) reductase (HMGCR) (52). Gene expression of HMGCR and other cholesterogenic proteins is induced by Sterol regulatory element-binding proteins (SREBP) (53, 55). Free cholesterol is transported into mitochondria by steroidogenic acute regulatory (StAR) protein, through a complex process involving a number of different proteins, such as Voltage-dependent anion channels (VDAC) and translocase of the outer mitochondrial membrane 40 (TOMM40) (, , –76, 107, 108). Cholesterol transfer from the ER to mitochondria is facilitated via ER-mitochondria contact sites, called mitochondria-associated membranes (MAMs) (31, 75). Fatty acid desaturase 2 (FADS2)-mediated increase in the PUFA content of mitochondrial phospholipids promotes cholesterol import into mitochondria (59). Moreover, arachidonic acid (AA) released from phospholipids by acyl-CoA thioesterase 2 (ACOT2) promotes steroidogenesis (96, 97). In mitochondria, steroidogenesis starts with the conversion of cholesterol to pregnenolone by CYP11A1 (27, 30).