The overlooked role of high-density lipoprotein in adrenal stress adaptation: the HDL/SCARB1 axis as a regulator of stress-induced steroidogenesis

Purpose of review This review examines the critical role of the high-density lipoprotein (HDL)/scavenger receptor class B type 1 (SCARB1) pathway in adrenal glucocorticoid production during stress, emphasizing recent mechanistic evidence and its clinical implications. Recent findings SCARB1 mediates the selective uptake of HDL-derived cholesteryl esters by adrenocortical cells, providing the cholesterol substrate needed for rapid glucocorticoid synthesis under stress. Experimental models show that loss of SCARB1 function abolishes stress-induced glucocorticoid production even when low-density lipoprotein (LDL) is abundant, confirming that LDL cannot substitute for HDL/SCARB1-mediated cholesterol delivery. ACTH rapidly upregulates SCARB1 expression and function, driving microvillar channel formation and enhancing cholesterol flux to mitochondria. Disruption of this pathway impairs the physiologic stress response and increases vulnerability to inflammatory complications. Human genetic data and clinical observations reinforce these findings and highlight the impact of hypoalphalipoproteinemia and SCARB1 defects on adrenal reserve. Summary The HDL/SCARB1 axis is essential for acute glucocorticoid synthesis and integrates lipid metabolism with endocrine and immune resilience. This shifts the focus from HDL-C from a passive biomarker to HDL to an active endocrine cofactor. Preserving HDL functionality and SCARB1 integrity should guide the design of HDL-targeted interventions, especially in patients at risk for sepsis, systemic inflammation, or adrenal insufficiency.