title: Attenuated corticosterone response to chronic ACTH stimulation in hepatic lipase-deficient mice: evidence for a role for hepatic lipase in adrenal physiology.
abstract: 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, which utilize lipoprotein cholesterol to synthesize glucocorticoids in response to pituitary ACTH. It is likely that the role of adrenal HL is to facilitate delivery of exogenous cholesterol for glucocorticoid synthesis. On this basis, we hypothesized that HL deficiency would blunt the glucocorticoid response to ACTH. Furthermore, because exogenous cholesterol also is derived from the LDL 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 analyzed by Kruskal-Wallis one-way ANOVA on ranks and pairwise multiple comparisons by Dunn's test. Our results demonstrate a trend toward 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.
authors.affiliation: Dept. of Pediatrics, Box 356320, Univ. of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA. hdichek@u.washington.edu
authors.forename: Helén L
authors.initials: HL
authors.lastname: Dichek
authors.forename: Nalini
authors.initials: N
authors.lastname: Agrawal
authors.forename: Nazim
authors.initials: N
authors.lastname: El Andaloussi
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D002784:Cholesterol / Q000032:analysis; D002788:Cholesterol Esters / Q000032:analysis; D008076:Cholesterol, HDL / Q000097:blood; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D008049:Lipase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D010316:Particle Size; D010750:Phosphoproteins / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D010750:Phosphoproteins; D011973:Receptors, LDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; C030087:lipoprotein triglyceride; D000098682:Steroidogenic Acute Regulatory Protein; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C410382:LIPG protein, human; D008049:Lipase; C495700:Lipc protein, mouse; D003345:Corticosterone