LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

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. 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. The production and subsequent secretion of glucocorticoids by adrenocortical cells of the zona fasciculata is dependent on the availability of the steroidogenic precursor cholesterol. Unesterified cholesterol is converted to glucocorticoids through a series of side-chain modifications by cytochrome P450 enzymes and hydroxysteroid dehydrogenases (1Sasano H. Localization of steroidogenic enzymes in adrenal cortex and its disorders.Endocr. J. 1994; 41: 471-482Crossref PubMed Scopus (82) Google Scholar). The intramitochondrial transfer of unesterified cholesterol by the enzyme steroidogenic acute regulatory protein is considered to be the rate-limiting step in the basal synthesis of glucocorticoids. In vitro studies using isolated adrenocortical cells have suggested that HDL and apoB-containing lipoproteins are able to provide cholesterol as source for the synthesis of glucocorticoids (2Gwynne J.T. Hess B. The role of high density lipoproteins in rat adrenal cholesterol metabolism and steroidogenesis.J. Biol. Chem. 1980; 255: 10875-10883Abstract Full Text PDF PubMed Google Scholar, 3Gwynne J.T. Hess B. Hughes T. Rountree R. Mahaffee D. The role of serum high density lipoproteins in adrenal steroidogenesis.Endocr. Res. 1984–1985; 10: 411-430Crossref PubMed Scopus (12) Google Scholar, 4Mason J.I. Robidoux W.F. Steroidogenesis in isolated cells and mitochondria of rat Snell adrenocortical carcinoma 494.Endocrinology. 1979; 105: 1230-1236Crossref PubMed Scopus (22) Google Scholar, 5Higashijima M. Nawata H. Kato K. Ibayashi H. Studies on lipoprotein and adrenal steroidogenesis: I. Roles of low density lipoprotein- and high density lipoprotein-cholesterol in steroid production in cultured human adrenocortical cells.Endocrinol. Jpn. 1987; 34: 635-645Crossref PubMed Scopus (35) Google Scholar). We and others have shown that under conditions where glucocorticoids are physiologically relevant (i.e., under stress), the exogenous uptake and intracellular processing of lipoprotein-associated cholesteryl esters becomes of crucial importance to maintain optimal adrenal glucocorticoid function in vivo. Probucol-induced depletion of plasma cholesterol associated with HDL and LDL in C57BL/6 wild-type mice is associated with a lower stress-induced glucocorticoid level (6Hoekstra M. Korporaal S.J. Li Z. Zhao Y. Van Eck M. Van Berkel T.J. Plasma lipoproteins are required for both basal and stress-induced adrenal glucocorticoid synthesis and protection against endotoxemia in mice.Am. J. Physiol. Endocrinol. Metab. 2010; 299: E1038-E1043Crossref PubMed Scopus (25) Google Scholar). In addition, a defect in the hydrolysis of lipoprotein-associated cholesteryl esters in hormone-sensitive lipase knockout (KO) mice is associated with adrenocortical hypofunction (7Li H. Brochu M. Wang S.P. Rochdi L. Côté M. Mitchell G. Gallo-Payet N. Hormone-sensitive lipase deficiency in mice causes lipid storage in the adrenal cortex and impaired corticosterone response to corticotropin stimulation.Endocrinology. 2002; 143: 3333-3340Crossref PubMed Scopus (61) Google Scholar). Furthermore, apolipoprotein A1 (APOA1) KO mice that virtually lack HDL particles and scavenger receptor BI (SR-BI) KO mice that exhibit an impaired uptake of cholesteryl esters from HDL show a parallel diminished adrenal glucocorticoid function (8Plump A.S. Erickson S.K. Weng W. Partin J.S. Breslow J.L. Williams D.L. Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production.J. Clin. Invest. 1996; 97: 2660-2671Crossref PubMed Scopus (164) Google Scholar, 9Hoekstra M. Ye D. Hildebrand R.B. Zhao Y. Lammers B. Stitzinger M. Kuiper J. Van Berkel T.J. Van Eck M. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production.J. Lipid Res. 2009; 50: 1039-1046Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 10Hoekstra M. Meurs I. Koenders M. Out R. Hildebrand R.B. Kruijt J.K. Van Eck M. Van Berkel T.J. Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting.J. Lipid Res. 2008; 49: 738-745Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Combined, these findings suggest that the uptake of HDL-cholesteryl esters by the adrenals is essential to maintain optimal glucocorticoid production in vivo. The HDL-associated enzyme lecithin-cholesterol acyltransferase (LCAT) mediates the synthesis of HDL-cholesteryl esters. Human subjects with a deleterious mutation on both alleles of the LCAT gene present with HDL deficiency, whereas heterozygotes typically have HDL cholesterol levels that are half of normal HDL cholesterol (11Santamarina-Fojo S. Lambert G. Hoeg J.M. Jr Brewer H.B. Lecithin-cholesterol acyltransferase: role in lipoprotein metabolism, reverse cholesterol transport and atherosclerosis.Curr. Opin. Lipidol. 2000; 11: 267-275Crossref PubMed Scopus (84) Google Scholar, 12Hovingh G.K. Hutten B.A. Holleboom A.G. Petersen W. Rol P. Stalenhoef A. Zwinderman A.H. de Groot E. Kastelein J.J. Kuivenhoven J.A. Compromised LCAT function is associated with increased atherosclerosis.Circulation. 2005; 112: 879-884Crossref PubMed Scopus (139) Google Scholar). Heterozygous and homozygous LCAT KO mice show a similar dose-dependent decrease in plasma HDL levels (13Sakai N. Vaisman B.L. Koch C.A. Hoyt Jr, R.F. Meyn S.M. Talley G.D. Paiz J.A. Brewer Jr, H.B. Santamarina-Fojo S. Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency.J. Biol. Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar) and thus represent a good mouse model to study the consequences of HDL-cholesteryl ester deficiency on general physiology. To delineate the quantitative contribution of HDL-associated cholesteryl esters to the adrenal glucocorticoid output, here we assessed adrenal glucocorticoid function in LCAT KO mice. LCAT KO mice (14Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I.J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) and C57BL/6 wild-type controls were bred in house and fed a regular chow diet ad libitum. Throughout the experiment both types of mice were housed in the same climate-controlled stable with a 12 h/12 h dark-light cycle and handled identically. Age-matched 10 to 12 week old C57BL/6 mice (n = 10) and LCAT mice (n = 8) were switched to a new cage and fasted overnight (∼18 h) before tail chop blood draws. After an additional 2 weeks, these mice were injected intraperitoneally with 200 μg human ACTH analog (ACTH [1–24]; tetracosactide) followed by tail blood draws at 1, 2, and 3 h after ACTH exposure. Six weeks after the start of experiment, the mice received an intraperitoneal 50 μg/kg sublethal dose of lipopolysaccharide (LPS) (Salmonella minnesota R595) followed by tail blood draws at 1, 2, and 3 h after LPS exposure. Mice were euthanized and tissue was harvested at 4 h after LPS exposure. Before all three types of stress, mice were bled through tail chop to obtain an average basal plasma corticosterone value of each mouse. An additional group of 12 week old LCAT KO (n = 4) and C57BL/6 mice (n = 11) was subjected to overnight fasting (18 h) and subsequently euthanized for tissue harvesting. Animal care and procedures were performed in accordance with the national guidelines for animal experimentation. All protocols were approved by the Ethics Committee for Animal Experiments of Leiden University. Plasma concentrations of free cholesterol, cholesteryl esters, and triglycerides were determined using enzymatic colorimetric assays. The cholesterol distribution over the different lipoproteins in plasma was analyzed by fractionation of 50 μl pooled plasma of each mouse genotype using a Superose 6 column (3.2 × 30 mm; Smart-system, Pharmacia). Free cholesterol and cholesteryl ester content of the effluent was determined using enzymatic colorimetric assays. Seven micrometer cryosections were prepared on a Leica CM3050-S cryostat. Cryosections were routinely stained with Oil red O for neutral lipid visualization. Nuclei were detected using a hematoxylin stain. Corticosterone levels in plasma were determined using the corticosterone 3H RIA Kit from ICN Biomedicals according to the protocol from the supplier. Tumor necrosis factor-α (TNF-α) protein levels were determined in plasma by ELISA (OptEIA kit, BD Biosciences Pharmingen, San Diego, CA) using the standard protocol. Gene expression analysis was performed essentially as described (15Hoekstra M. Kruijt J.K. Van Eck M. Van Berkel T.J. Specific gene expression of ATP-binding cassette transporters and nuclear hormone in rat and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of were reverse and quantitative analysis was on the using an CA) according to the and were as genes for analysis was performed using Diego, of the was using the of and The of was using a or where were considered In accordance with a role for LCAT in the of free cholesterol A. Lecithin-cholesterol acyltransferase in the metabolism of PubMed Scopus Google LCAT KO mice an complete of cholesteryl esters P < 0.001) in plasma with plasma free cholesterol levels a the free cholesterol to cholesteryl ester ratio was 8-fold higher (P < 0.001) in plasma from LCAT KO mice as compared with C57BL/6 wild-type control mice lipoprotein analysis that free cholesterol and cholesteryl ester levels in C57BL/6 wild-type mice were associated with the HDL and virtually cholesteryl esters were present in the HDL in plasma of LCAT KO whereas the cholesteryl ester content was essentially The HDL-associated free cholesterol level was lower in LCAT KO mice as compared with C57BL/6 mice In contrast, the level of free cholesterol associated with apoB-containing lipoproteins was higher in plasma of LCAT KO mice In with an increased of apoB-containing and LDL particles in plasma of LCAT knockout as by (13Sakai N. Vaisman B.L. Koch C.A. Hoyt Jr, R.F. Meyn S.M. Talley G.D. Paiz J.A. Brewer Jr, H.B. Santamarina-Fojo S. Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency.J. Biol. Chem. 1997; 272: 7506-7510Abstract Full Text Full Text PDF PubMed Scopus (107) Google we detected a significantly higher level of plasma triglycerides (44%; P < in LCAT KO mice in wild-type C57BL/6 and LCAT KO cholesterol esters cholesterol in a new The basal secretion of glucocorticoids by adrenals in mice is low and is to be of the acquisition of cholesterol de production of cholesterol from be to maintain basal However, the to (P = we a marked decrease in basal plasma levels of glucocorticoid in response to LCAT deficiency for LCAT KO mice for C57BL/6 of the in the secretion of glucocorticoids by the adrenals at levels that glucocorticoid receptor an essential of the response to adrenocortical the of a of the hormone ACTH 200 μg adrenal associated with an acute in plasma corticosterone levels in C57BL/6 wild-type mice. Plasma corticosterone a at h after the 3 h after the increased plasma corticosterone levels in LCAT KO the of corticosterone in plasma of LCAT KO mice was lower the level detected in C57BL/6 mice after h of P < 0.001) In to wild-type the of corticosterone in LCAT KO mice after h and to basal levels at 3 h that the adrenals of LCAT KO mice are of a glucocorticoid response of the glucocorticoids against and J.I. E.M. of the glucocorticoids and glucocorticoid in of to and Endocrinol. PubMed Scopus Google Scholar). In with an essential role for glucocorticoids in the response to to a sublethal dose of 50 μg/kg a in plasma corticosterone levels in C57BL/6 a of at 2 h after Plasma corticosterone levels in LCAT KO mice However, LCAT KO mice a to 3 h after LPS was lower as compared with the level in C57BL/6 mice P < 0.001) The plasma corticosterone levels for C57BL/6 mice for LCAT KO and the for C57BL/6 mice for LCAT KO were similar for genotype after and exposure. is suggested that both a acute adrenal steroid output, is 40–50% lower in LCAT KO mice. through of the nuclear glucocorticoid are important of and overnight fasting is associated with an of adrenal glucocorticoid secretion to M. Meurs I. Koenders M. Out R. Hildebrand R.B. Kruijt J.K. Van Eck M. Van Berkel T.J. Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting.J. Lipid Res. 2008; 49: 738-745Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Lambert G. Y. S.J. Apolipoprotein is by and of and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, D. S. S. H. H. T. H. T. 2 receptor is required for adrenal and PubMed Scopus Google Scholar). In with after h of fasting we lower (P < 0.001) corticosterone levels in LCAT KO mice as compared with C57BL/6 control mice Combined, these findings suggest that HDL deficiency in LCAT KO mice is associated with a diminished adrenal corticosterone output in response to in the of the adrenals LCAT KO mice and C57BL/6 mice endotoxemia (i.e., 4 h after LPS or under fasting stress conditions was (14Ng D.S. Francone O.L. Forte T.M. Zhang J. Haghpassand M. Rubin E.M. Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I.J. Biol. Chem. 1997; 272: 15777-15781Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) have described that adrenals from LCAT knockout mice are under normal conditions of cholesteryl esters. In our group of LCAT KO deficiency of neutral in adrenocortical cells be using Oil red O neutral lipid from the adrenocortical cells within the zona fasciculata in LCAT KO mice lack the Oil red O as in the mice. The unesterified cholesterol for can be by synthesis of cholesterol in the rate-limiting step hydrolysis of cholesteryl esters, or uptake of exogenous lipoprotein-associated cholesterol. To compensatory gene using quantitative we gene expression levels in adrenals harvested from LCAT KO mice and C57BL/6 wild-type control mice of (P < 0.001) expression levels was detected in the adrenals of LCAT KO mice. The expression levels of enzymes involved in synthesis and hydrolysis of cholesteryl esters within the adrenals were scavenger receptor BI (SR-BI) expression was whereas the LDL receptor expression level was significantly increased P < 0.001) in LCAT KO mice. thus that adrenals of LCAT KO mice as compared with of wild-type control as a compensatory to cholesterol and increased of through The glucocorticoid receptor is in where J. E. for to glucocorticoid N. Y. 2009; PubMed Scopus Google Scholar) and in where metabolism T.J. K. mice an glucocorticoid are glucocorticoid Endocrinol. PubMed Scopus Google Scholar). glucocorticoid is associated with an J. of in production and I. In regulatory the and necrosis Full Text PDF PubMed Scopus Google Scholar, R. M. P. mice to the of and necrosis PubMed Scopus Google we determined the of LCAT deficiency on the Plasma levels of the response were not significantly different at after LPS μg/kg h) thus that LCAT KO and C57BL/6 wild-type mice a similar glucocorticoid receptor level in after LPS exposure. LCAT expression was in of LCAT KO mice (P < 0.001) The expression level of the gene apolipoprotein Lambert G. Y. S.J. Apolipoprotein is by and of and Lipid Res. Full Text Full Text PDF PubMed Scopus Google was significantly in of LCAT KO mice P < Furthermore, LCAT deficiency was associated with a marked (P < 0.001) in the expression level of the glucocorticoid protein gene expression level in is to control by glucocorticoids T.J. I. N. R. Z. The glucocorticoid receptor is essential for basal and of the murine Endocrinol. PubMed Scopus Google Scholar). glucocorticoid receptor to be in within the of LCAT KO mice. Combined, these findings suggest that LCAT KO mice not from glucocorticoid glucocorticoid is that both HDL and apoB-containing lipoproteins can be as of cholesterol for the production of glucocorticoids by adrenocortical the contribution of the lipoprotein to in is not In the we assessed glucocorticoid function in LCAT KO mice to the contribution of HDL-associated cholesteryl esters to adrenal high cholesterol levels and a compensatory up-regulation of genes associated with adrenal cholesterol LCAT KO mice that lack HDL-cholesteryl esters are to a glucocorticoid response lower as compared with C57BL/6 wild-type control to three types of stress LPS exposure, and overnight The cholesteryl ester is significantly changed in LCAT KO mice J.S. Li H. N. of apolipoprotein A-I deficiency on lecithin:cholesterol acyltransferase in mouse Lipid Res. Full Text PDF PubMed Google can the adrenal glucocorticoid output for transfer and uptake of high density lipoprotein cholesteryl Lipid Res. Full Text PDF PubMed Google Scholar). However, of from pooled plasma of C57BL/6 and LCAT KO mice (n = using that both types of mice not have high levels of to in vitro studies using adrenocortical cells not that in the cholesteryl ester are to have a on the glucocorticoid in LCAT KO mice. We thus our findings that HDL-associated cholesteryl esters an essential contribution to in adrenal glucocorticoid from studies in human subjects further LCAT deficiency in is associated with a lower adrenal steroid output as by a decrease in the of and Holleboom A.G. M. Kuivenhoven J.A. G.K. adrenal steroid production in with low HDL cholesterol to in and in on Scholar). from SR-BI KO mice that lack a HDL receptor that adrenal uptake of cholesteryl esters from HDL is associated with glucocorticoid these mice a glucocorticoid and an to endotoxemia M. Ye D. Hildebrand R.B. Zhao Y. Lammers B. Stitzinger M. Kuiper J. Van Berkel T.J. Van Eck M. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production.J. Lipid Res. 2009; 50: 1039-1046Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 10Hoekstra M. Meurs I. Koenders M. Out R. Hildebrand R.B. Kruijt J.K. Van Eck M. Van Berkel T.J. Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting.J. Lipid Res. 2008; 49: 738-745Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, L. A. de SR-BI against endotoxemia in mice through its in glucocorticoid production and Clin. Invest. 2008; PubMed Scopus Google Scholar). In the study we that LCAT KO mice that lack HDL-cholesteryl esters diminished glucocorticoid in exhibit a expression level and a compensatory up-regulation of In with a lower glucocorticoid in LCAT KO D.S. E. in lecithin-cholesterol mice is associated with of increased and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) have detected a lower expression level of the gene and a parallel decrease in plasma levels in response to LCAT deficiency. In to the in glucocorticoid in LCAT KO glucocorticoid is normal in these mice the to endotoxemia is a in glucocorticoid (i.e., high glucocorticoid receptor in and low glucocorticoid receptor in detected in our and adrenal studies Van Berkel T.J. M. the of by adrenal Full Text Full Text PDF PubMed Scopus Google Scholar). SR-BI knockout mice thus a glucocorticoid that in LCAT KO mice. SR-BI is the involved in the uptake of HDL-associated cholesteryl esters R. M. J.A. Kruijt J.K. Eck M. J. Van Berkel T.J. Scavenger receptor class B type is for the uptake of cholesteryl esters from HDL by the and the adrenals in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). both types of mice glucocorticoid we that the is essential to the of corticosterone to the glucocorticoid receptor in However, the in glucocorticoid and endotoxemia the LCAT and SR-BI knockout mice to on a HDL-cholesteryl corticosterone SR-BI knockout mice to plasma corticosterone levels in response to LPS M. Ye D. Hildebrand R.B. Zhao Y. Lammers B. Stitzinger M. Kuiper J. Van Berkel T.J. Van Eck M. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production.J. Lipid Res. 2009; 50: 1039-1046Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, L. A. de SR-BI against endotoxemia in mice through its in glucocorticoid production and Clin. Invest. 2008; PubMed Scopus Google whereas the present study that LCAT KO mice are able to to a lower plasma glucocorticoid levels in response to our LCAT KO mice and SR-BI KO mice M. Ye D. Hildebrand R.B. Zhao Y. Lammers B. Stitzinger M. Kuiper J. Van Berkel T.J. Van Eck M. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production.J. Lipid Res. 2009; 50: 1039-1046Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar) an in the adrenal expression level of the LDL the protein involved in the of apoB-containing lipoproteins as and findings by S. J. S. S. The LDL receptor is not for acute adrenal in mouse adrenocortical J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar) have suggested that the LDL receptor not cholesterol the steroidogenic a role for the LDL in the synthesis of corticosterone in LCAT KO mice can be SR-BI is able to apoB-containing lipoproteins D. M. J. D. L. L. The role of human and mouse scavenger receptor class B type (SR-BI) in the uptake of PubMed Scopus Google Scholar, S. S. Williams D.L. Scavenger receptor class type mediates uptake of low density lipoprotein cholesteryl Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Eck M. M. Out R. Kruijt J.K. Hildebrand R.B. Van Berkel T.J. Scavenger receptor BI the metabolism of lipoproteins in Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus (82) Google Scholar). LCAT KO in to SR-BI KO thus cholesteryl esters from particles through uptake by is to maintain plasma glucocorticoid levels that the glucocorticoid receptor in not studies with specific SR-BI that are for HDL or and the associated as by for the group of R. M. of the high density lipoprotein and low density lipoprotein of murine scavenger receptor class B type using Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google show the contribution of the to adrenal steroid In conclusion, our studies show that HDL-cholesteryl ester deficiency in LCAT KO mice is associated with a 40–50% lower adrenal glucocorticoid stress response as a a glucocorticoid These findings further highlight the important novel role for HDL as cholesterol donor for the synthesis of glucocorticoids by the adrenals. The from the of of in The for knockout lipopolysaccharide scavenger receptor BI necrosis factor-α

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