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Hormone-Sensitive Lipase Deficiency in Mice Causes Lipid Storage in the Adrenal Cortex and Impaired Corticosterone Response to Corticotropin Stimulation

Service de Génétique Médicale (H.L., S.P.W., G.M.), Département d’Obstétrique (M.B.), Hôpital Ste-Justine, Montréal, Canada H3T 1C5; and Service d’endocrinologie (L.R., M.C., N.G.-P.), Département de Médecine, Université de Sherbrooke, Sherbrooke, Canada J1H 5N4

Address all correspondence and requests for reprints to: Dr. Nicole Gallo-Payet, Service of Endocrinology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, Québec, Canada J1H 5N4. E-mail: n.gallo{at}courrier.usherb.ca.

Hormone-sensitive lipase (HSL, E.C.3.1.1.3, gene designation Lipe) is reportedly the major cholesteryl esterase of adrenal cortex. Because of the potential importance of cholesteryl ester hydrolysis in steroidogenesis, gene-targeted HSL-deficient mice were assessed for adrenal cortical morphology and function. Compared with control animals, HSL deficiency results in a marked accumulation of lipid droplets both in zona glomerulosa and zona fasciculata. In the zona fasciculata, lipid accumulation was observed progressively from the outer to the inner regions, culminating near the corticomedullary junction with the formation of syncytial-lipoid structures having the appearance of degenerative cells. These morphological changes did not significantly alter the basal levels of circulating corticosterone, but following ACTH stimulation, corticosterone levels were decreased (P < 0.001). The observation of normal basal corticosterone and aldosterone levels demonstrates that some free cholesterol for steroid synthesis can be produced independently of HSL. Taken together, these results indicate that HSL-deficient mice accumulate lipid droplets in such a way as to impair acute ACTH stimulation of corticosterone secretion. Such observations are also found in some forms of congenital adrenal hyperplasia. By extension, HSL deficiency may be a cause of hereditary adrenocortical hypofunction in humans.

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