Abstract
The adrenal gland is one of the prominent sites for steroid hormone synthesis. Lipoprotein-derived cholesterol esters (CEs) delivered via SR-B1 constitute the dominant source of cholesterol for steroidogenesis, particularly in rodents. Adrenocorticotropic hormone (ACTH) stimulates steroidogenesis through downstream actions on multiple components involved in steroidogenesis. Both acute and chronic ACTH treatments can modulate SR-B1 function, including its transcription, posttranscriptional stability, phosphorylation and dimerization status, as well as the interaction with other protein partners, all of which result in changes in the ability of SR-B1 to mediate HDL-CE uptake and the supply of cholesterol for conversion to steroids. Here, we provide a review of the recent findings on the regulation of adrenal SR-B1 function by ACTH.
Highlights
Reviewed by: Tamas Kozicz, Radboud University Medical Center, Netherlands Frédéric Gachon, Nestlé Institute of Health Sciences, Switzerland
Cholesterol is the common precursor for steroidogenesis, which involves the contribution from multiple enzymes and requires the conversion of cholesterol to pregnenolone as the initial step of a multistep process
Pregnenolone is subsequently metabolized to produce various biologically active steroids in a tissue-specific manner. This process is thought to involve five major steps: [1] cholesterol acquisition through de novo synthesis and/or uptake from lipoproteins and stored as cholesterol esters (CEs) in lipid droplets (LDs), [2] cholesterol mobilization from CEs that are stored in LDs, [3] trafficking of cholesterol to the cytochrome P450 side-chain cleavage enzyme (P450scc, CYP11A1) at the inner mitochondrial membrane (IMM), following cholesterol trafficking to the outer mitochondrial membrane (OMM), [4] production of pregnenolone by CYP11A1 through cleavage of the cholesterol side-chain, and [5] efflux of pregnenolone from the mitochondria to the endoplasmic reticulum (ER), where enzymes convert it into intermediates that shuttle between mitochondria and ER to produce progestins, estrogens, androgens, glucocorticoids, or mineralocorticoids in a tissue-specific manner [2, 5]
Summary
Initial studies established a functional correlation between SR-B1 expression, HDL-CE uptake, and the ability of steroidogenic cells to produce steroid hormones [8, 35,36,37,38,39,40]. In one of our recent studies, the level of SR-B1 protein in rat adrenals shows a trend for increased SR-B1 expression as early as 1 h after treatment with ACTH [45].
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