Hepatic lipase (HL), a liver-expressed lipolytic enzyme, hydrolyzes triglycerides and phospholipids in lipoproteins and promotes cholesterol delivery through receptor-mediated whole particle and selective cholesterol uptake. HL activity also occurs in the adrenal glands that utilize lipoprotein cholesterol to synthesize glucocorticoids in response to pituitary adrenocorticotropic hormone (ACTH). It is likely that the role of adrenal HL is to facilitate delivery of exogenous cholesterol for glucocorticoid synthesis. Based on this, we hypothesized that HL deficiency would blunt the glucocorticoid response to ACTH. Furthermore, because exogenous cholesterol also is derived from the low density lipoprotein receptor (LDLR)-pathway, we hypothesized that LDLR-deficiency would blunt the response to ACTH. To test these hypotheses, we compared the corticosterone response to eight daily ACTH injections in HL-deficient (hl-/-), LDLR-deficient (Ldlr-/-) and HL and LDLR-doubly deficient (Ldlr-/-hl-/-) mice with that in wild-type (WT) mice. Plasma corticosterone levels were measured on days 2, 5 and 8. Differences in plasma corticosterone levels between genotypes were analysed by Kruskal-Wallis One Way Analysis of Variance on Ranks and Pairwise Multiple Comparisons by Dunn's test. Our results demonstrate a trend towards reductions in plasma corticosterone levels on day 2 and significant reductions on day 5 and day 8 in the knockout models. Thus, on day 5, plasma corticosterone levels were reduced by 57 %, 70 % and 73 %, all p< 0.05 ., and on day 8 by 76%, 59%, and 63%, all p < 0.05, in hl-/-, Ldlr-/- and Ldlr-/-hl-/- mice respectively. These results demonstrate that HL-deficiency, like LDLR deficiency, blunts the adrenal response to chronic ACTH stimulation and suggest a novel role for HL in adrenal physiology.