The Roles of Circulating High-Density Lipoproteins and Trophic Hormones in the Phenotype of Knockout Mice Lacking the Steroidogenic Acute Regulatory Protein

Abstract

The steroidogenic acute regulatory protein (StAR) is essential for the regulated production of steroid hormones, mediating the translocation of intracellular cholesterol to the inner mitochondrial membrane where steroidogenesis begins. Steroidogenic cells lacking StAR have impaired steroidogenesis and progressively accumulate lipid, ultimately causing cytopathic changes and deterioration of steroidogenic capacity. Developmental studies of StAR knockout (KO) mice have correlated gonadal lipid deposits with puberty, suggesting that trophic hormones contribute to this lipid accumulation. To delineate the role of gonadotropins in this process, we examined double mutant mice deficient in both StAR and gonadotropins [StAR KO/hpg (hypogonadal)]. Lipid accumulation was ameliorated considerably in StAR KO/hpg mice but was restored by treatment with exogenous gonadotropins, directly linking trophic hormones with gonadal lipid accumulation. To define the relative roles of exogenous vs. endogenous cholesterol in the lipid accumulation, we also examined mice lacking both StAR and apolipoprotein A-I (StAR KO/Apo A-I KO). Steroidogenic tissues of StAR KO/Apo A-I KO mice had markedly decreased lipid deposits, supporting the predominant role of high-density lipoprotein-derived cholesterol in the lipid accumulation caused by StAR deficiency. Finally, we used electron microscopy to compare mitochondrial ultrastructure in StAR KO and cholesterol side-chain cleavage enzyme (Cyp11a1) KO mice; despite comparable lipid accumulation within adrenocortical cells, the effects of StAR deficiency and Cyp11a1 deficiency on mitochondrial ultrastructure were markedly different. These findings extend our understanding of steroidogenic cell dysfunction in StAR KO mice and highlight key roles of trophic hormones and high-density lipoprotein-derived cholesterol in lipid deposits within StAR-deficient steroidogenic cells.

Fetal Glucocorticoid Synthesis Is Required for Development of Fetal Adrenal Medulla and Hypothalamus Feedback Suppression

“…The number of cristae in the mitochondria is reduced in StAR null mice (37). We detected mitochondria defect in Cyp11a1-deficient mice as early as E9.5 in placenta (data not shown), in E18.5 adrenal, and also in a mild Cyp11a1 promoter mutant as late as 18-wk-old adrenal glands (40).…”

Parallel early development of zebrafish interrenal glands and pronephros:differential control bywt1andff1b

“…Those affected suffer from insufficient corticosteroid secretion resulting in virilization and salt wasting. Knockout mice deficient in steroidogenic genes like Star and P450scc have been generated to investigate the molecular mechanism of adrenal insufficiencies (Caron et al, 1997;Hu et al, 2002;Ishii et al, 2002). Despite extensive investigation into the molecular bases of these diseases, very little is known about the early events leading to the formation of functional adrenal glands.…”

Liver X receptor opens a new gateway to StAR and to steroid hormones

“…The hormonal regulation (6) and mechanism of cholesterol intermembrane transfer (3) are complex. Loss of StAR in either humans or mice leads to dramatic increases in the level of cholesterol esters in adrenal cortex cells and associated adrenal hyperplasia, which arises secondary to a loss of glucocorticoids and a compensatory rise in ACTH (7).…”