Adrenocortical LDL receptor function negatively influences glucocorticoid output.

Area of Science:

• Endocrinology
• Molecular Biology
• Lipid Metabolism

Background:

• Adrenocortical cells require significant cholesterol for glucocorticoid synthesis, with over 50% sourced from lipoproteins.
• The specific roles of different lipoproteins and their uptake mechanisms in adrenal steroidogenesis are not fully understood.

Purpose of the Study:

• To investigate the in vivo significance of low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake in adrenal steroidogenesis.
• To elucidate the impact of LDLR function on glucocorticoid production under basal and stressed conditions.

Main Methods:

• Utilized female total body LDLR knockout mice with a human-like lipoprotein profile.
• Employing adrenal autotransplantation under the renal capsule to modulate adrenocortical LDLR expression.
• Measured plasma corticosterone levels and analyzed gene expression of steroidogenic enzymes.

Main Results:

• Restoring adrenal LDLR function significantly attenuated ACTH-stimulated corticosterone production (44-59% reduction).
• LDLR-expressing adrenal transplants showed a 39% decrease in plasma corticosterone under fasting stress.
• A 62% reduction in HSD3B2 transcript levels was observed in LDLR-expressing adrenal transplants, without changes in cholesterol mobilization genes.

Conclusions:

• Provides the first in vivo evidence for an inhibitory role of the LDLR in controlling adrenal glucocorticoid production.
• Suggests LDLR-mediated cholesterol uptake influences steroidogenesis through mechanisms beyond cholesterol mobilization, potentially impacting HSD3B2 expression.