title: LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function.
abstract: In vitro studies have suggested that HDL and apoB-containing lipoproteins can provide cholesterol for synthesis of glucocorticoids. Here we assessed adrenal glucocorticoid function in LCAT knockout (KO) mice to determine the specific contribution of HDL-cholesteryl esters to adrenal glucocorticoid output in vivo. LCAT KO mice exhibit an 8-fold higher plasma free cholesterol-to-cholesteryl ester ratio (P < 0.001) and complete HDL-cholesteryl ester deficiency. ApoB-containing lipoprotein and associated triglyceride levels are increased in LCAT KO mice as compared with C57BL/6 control mice (44%; P < 0.05). Glucocorticoid-producing adrenocortical cells within the zona fasciculata in LCAT KO mice are devoid of neutral lipids. However, adrenal weights and basal corticosterone levels are not significantly changed in LCAT KO mice. In contrast, adrenals of LCAT KO mice show compensatory up-regulation of genes involved in cholesterol synthesis (HMG-CoA reductase; 516%; P < 0.001) and acquisition (LDL receptor; 385%; P < 0.001) and a marked 40-50% lower glucocorticoid response to adrenocorticotropic hormone exposure, endotoxemia, or fasting (P < 0.001 for all). In conclusion, our studies show that HDL-cholesteryl ester deficiency in LCAT KO mice is associated with a 40-50% lower adrenal glucocorticoid output. These findings further highlight the important novel role for HDL as cholesterol donor for the synthesis of glucocorticoids by the adrenals.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands. hoekstra@lacdr.leidenuniv.nl
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Veronica
authors.initials: V
authors.lastname: Hirsch-Reinshagen
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Bochem
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D055786:Gene Knockout Techniques; D005938:Glucocorticoids / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002788:Cholesterol Esters; D005938:Glucocorticoids; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D003345:Corticosterone