High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans. Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans. The synthesis and secretion of adrenal steroid hormones for regulating stress responses, electrolyte homeostasis, and maintenance of secondary sexual characteristics depends upon the availability of the precursor cholesterol (1Hu J. Zhang Z. Shen W.J. Azhar S. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones.Nutr. Metab. (Lond.). 2010; 7: 47Crossref PubMed Scopus (293) Google Scholar). To secure a continuous cholesterol supply, the adrenal glands can synthesize cholesterol, metabolize intracellular esterified cholesterol, or obtain cholesterol from circulating lipoproteins (1Hu J. Zhang Z. Shen W.J. Azhar S. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones.Nutr. Metab. (Lond.). 2010; 7: 47Crossref PubMed Scopus (293) Google Scholar). Although exact data are lacking, plasma lipoproteins have been suggested to contribute more than 75% of all cholesterol required for adrenal steroidogenesis (2Borkowski A. Delcroix C. Levin S. Metabolism of adrenal cholesterol in man. I. In vivo studies.J. Clin. Invest. 1972; 51: 1664-1678Crossref PubMed Scopus (33) Google Scholar, 3Borkowski A.J. Levin S. Delcroix C. Mahler A. Verhas V. Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation.J. Clin. Invest. 1967; 46: 797-811Crossref PubMed Scopus (70) Google Scholar), but the current literature gives little insight in associations between plasma lipoprotein levels and adrenal function in humans. With respect to a role for low-density lipoprotein (LDL), it has been shown that LDL receptor-deficient patients suffering from familial hypercholesterolemia display normal urinary excretion of both 17 hydroxycorticosteroids (17-OHCS) and 17 ketogenic steroid metabolites (17-KS) indicative of unaffected adrenal function (4Illingworth D.R. Lees A.M. Lees R.S. Adrenal cortical function in homozygous familial hypercholesterolemia.Metabolism. 1983; 32: 1045-1052Abstract Full Text PDF PubMed Scopus (49) Google Scholar, 5Illingworth D.R. Alam N.A. Lindsey S. Adrenocortical response to adrenocorticotropin in heterozygous familial hypercholesterolemia.J. Clin. Endocrinol. Metab. 1984; 58: 206-211Crossref PubMed Scopus (21) Google Scholar). In addition, low or absent LDL cholesterol (LDL-C) in carriers of one or two defective APOB alleles respectively did not affect basal adrenal function either (6Illingworth D.R. Kenny T.A. Orwoll E.S. Adrenal function in heterozygous and homozygous hypobetalipoproteinemia.J. Clin. Endocrinol. Metab. 1982; 54: 27-33Crossref PubMed Scopus (70) Google Scholar). Combined this suggests that LDL is probably not playing a major role in delivering cholesterol for steroid hormone production in humans. Associations with HDL cholesterol (HDL-C) have thus far only been studied in critically ill patients. In one study it was shown that low HDL-C in such patients was associated with attenuated adrenal responses to synthetic adrenocorticotropic hormone (ACTH) (7van der Voort P.H. Gerritsen R.T. Bakker A.J. Boerma E.C. Kuiper M.A. de Heide L. HDL-cholesterol level and cortisol response to synacthen in critically ill patients.Intensive Care Med. 2003; 29: 2199-2203Crossref PubMed Scopus (55) Google Scholar). In support of this, others reported a high incidence of adrenal failure in critically ill individuals with liver disease, with HDL-C being the only variable predictive of adrenal insufficiency (8Marik P.E. Gayowski T. Starzl T.E. The hepatoadrenal syndrome: a common yet unrecognized clinical condition.Crit. Care Med. 2005; 33: 1254-1259Crossref PubMed Scopus (175) Google Scholar). Using adrenal cells, it has been suggested that HDL is the preferred lipoprotein for cholesterol delivery to the adrenal gland (9Yaguchi H. Tsutsumi K. Shimono K. Omura M. Sasano H. Nishikawa T. Involvement of high density lipoprotein as substrate cholesterol for steroidogenesis by bovine adrenal fasciculo-reticularis cells.Life Sci. 1998; 62: 1387-1395Crossref PubMed Scopus (44) Google Scholar) and in accordance, scavenger receptor type B1 (SRB1)-mediated cholesterol uptake from HDL has been shown to be the predominant source of cholesterol in mice (10Azhar S. Reaven E. Scavenger receptor class BI and selective cholesteryl ester uptake: partners in the regulation of steroidogenesis.Mol. Cell. Endocrinol. 2002; 195: 1-26Crossref PubMed Scopus (156) Google Scholar, 11Azhar S. Leers-Sucheta S. Reaven E. Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and 'selective’ pathway connection.Front. Biosci. 2003; 8: s998-s1029Crossref PubMed Scopus (78) Google Scholar, 12Reaven E. Chen Y.D. Spicher M. Azhar S. Morphological evidence that high density lipoproteins are not internalized by steroid-producing cells during in situ organ perfusion.J. Clin. Invest. 1984; 74: 1384-1397Crossref PubMed Scopus (94) Google Scholar–13Azhar S. Stewart D. Reaven E. Utilization of cholesterol-rich lipoproteins by perfused rat adrenals.J. Lipid Res. 1989; 30: 1799-1810Abstract Full Text PDF PubMed Google Scholar). In line, it has been shown that mice lacking SRB1 display an impaired adrenal glucocorticoid stress response (14Hoekstra 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, 15Hoekstra 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 (59) Google Scholar), lending support to a major role for HDL as a cholesterol donor in mice. In humans, we also showed that adrenal function was compromised in individuals with a functional mutation in SCARB1, the gene encoding SRB1 (16Vergeer M. Korporaal S.J. Franssen R. Meurs I. Out R. Hovingh G.K. Hoekstra M. Sierts J.A. Dallinga-Thie G.M. Motazacker M.M. et al.Genetic variant of the scavenger receptor BI in humans.N. Engl. J. Med. 2011; 364: 136-145Crossref PubMed Scopus (266) Google Scholar). While this study showed that cholesterol delivery to the adrenals via the HDL-SRB1 pathway is important for adrenal steroidogenesis in humans, it is unclear whether plasma HDL-C levels are associated with adrenal steroidogenesis in humans. To investigate this, we assessed basal and ACTH-stimulated adrenal cortical function in males with low HDL-C due to mutations in either ATP binding cassette transporter 1 (ABCA1) (17Candini C. Schimmel A.W. Peter J. Bochem A.E. Holleboom A.G. Vergeer M. Dullaart R.P. Dallinga-Thie G.M. Hovingh G.K. Khoo K.L. et al.Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.Atherosclerosis. 2010; 213: 492-498Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) or lecithin:cholesterol acyltransferase (LCAT) and in subjects with low HDL-C without mutations in ABCA1/LCAT, as well as in normolipidemic controls (18Duivenvoorden R. de Groot E. Elsen B.M. Lameris J.S. van der Geest R.J. Stroes E.S. Kastelein J.J. Nederveen A.J. In vivo quantification of carotid artery wall dimensions: 3.0-Tesla MRI versus B-mode ultrasound imaging.Circ. Cardiovasc. Imaging. 2009; 2: 235-242Crossref PubMed Scopus (69) Google Scholar). We hypothesized that in subjects with low HDL-C levels, adrenal function would be compromised irrespective of the molecular origin of the low HDL-C. Male subjects with HDL-C levels below the fifth percentile were screened for mutations in ABCA1 and LCAT (17Candini C. Schimmel A.W. Peter J. Bochem A.E. Holleboom A.G. Vergeer M. Dullaart R.P. Dallinga-Thie G.M. Hovingh G.K. Khoo K.L. et al.Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.Atherosclerosis. 2010; 213: 492-498Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 19Duivenvoorden R. Holleboom A.G. van den Bogaard B. Nederveen A.J. de Groot E. Hutten B.A. Schimmel A.W. Hovingh G.K. Kastelein J.J. Kuivenhoven J.A. et al.Cholesterol acyltransferase gene mutations have accelerated atherogenesis as assessed by carotid 3.0-T magnetic resonance imaging.J. Am. Coll. Cardiol. 2011; 58: 2481-2487Crossref PubMed Scopus (49) Google Scholar), of which the functionality was assessed in previously published studies (17Candini C. Schimmel A.W. Peter J. Bochem A.E. Holleboom A.G. Vergeer M. Dullaart R.P. Dallinga-Thie G.M. Hovingh G.K. Khoo K.L. et al.Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.Atherosclerosis. 2010; 213: 492-498Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 20van Dam M.J. de Groot E. Clee S.M. Hovingh G.K. Roelants R. Brooks-Wilson A. Zwinderman A.H. Smit A.J. Smelt A.H. Groen A.K. et al.Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.Lancet. 2002; 359: 37-42Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 21Holleboom A.G. Kuivenhoven J.A. Peelman F. Schimmel A.W. Peter J. Defesche J.C. Kastelein J.J. Hovingh G.K. Stroes E.S. Motazacker M.M. High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in The Netherlands: identification and characterization of eight novel mutations.Hum. Mutat. 2011; 32: 1290-1298Crossref PubMed Scopus (32) Google Scholar). For the current study, we enrolled 24 carriers of mutations in the ABCA1 gene. We furthermore enrolled 40 male carriers of mutations in the LCAT gene. In addition, subjects with similarly reduced HDL-C levels without mutations in ABCA1 and LCAT were included (n = 11). As a control group, normolipidemic age-matched male individuals were recruited by advertisement. None of the included individuals used medication interfering with steroid metabolism. The study was approved by the institutional review board of the Academic Medical Center, Amsterdam, The Netherlands and all participants provided written informed consent. Medical history, cardiovascular risk factors, use of medication, and family history of cardiovascular disease were assessed using a questionnaire. Brachial artery blood pressures were measured using an oscillometric blood pressure device (Omron 705IT, Hoofddorp, The Netherlands). Hypertension was defined as 1) use of antihypertensive medication, or 2) a systolic blood pressure at visit above 140 mm Hg and/or diastolic blood pressure above 90 mm Hg. Plasma was obtained after an overnight fast and stored at −80°C. Total cholesterol, LDL-C, HDL-C, and triglyceride levels were analyzed using commercially available enzymatic methods (Randox, Antrim, UK and Wako, Neuss, Germany) on a Cobas Mira autoanalyzer (Roche, Basel, Switzerland). Free cholesterol and total cholesterol were measured before and after precipitation of apoB-containing lipoproteins using phosphotungstic acid (Sigma) and a commercially available enzymatic assay (Diasys) on a Selectra autoanalyzer (Sopachem). ACTH was determined by an immunoluminometric assay (Nichols Institute, Los Angeles, CA). Aldosterone was measured using a radioimmunoassay (Siemens, Los Angeles, CA). Urinary excretion of steroid metabolites was analyzed by gas chromatography in 24 h urine samples as previously described (22van de Calseyde J.F. Scholtis R.J. Schmidt N.A. Leijten C.J. Profiling urinary steroids. A reliable procedure.Clin. Chim. 1972; PubMed Scopus Google Scholar, T.J. Schmidt N.A. A.J. van de Calseyde J.F. for 1989; PubMed Scopus Google Scholar). and were measured as of adrenal steroidogenesis. and the total and were the of the total In addition, urinary cortisol was determined using on a The was on was on a using with acid as and as B. of total assay of seven ABCA1 and seven LCAT mutation carriers to an ACTH stimulation study or The Netherlands). an overnight participants at blood samples were and 1 before of the 1 blood samples were and after Plasma cortisol levels were measured by Medical Los Angeles, and cortisol binding levels were measured with a radioimmunoassay Medical Free cortisol levels were using the described by van and van H. use of plasma cortisol as from total cortisol and PubMed Scopus Google Scholar). was for of continuous data with a normal In of a data were to data were assessed by A P of was A was used to for differences in and We enrolled 24 and 40 carriers of mutations in either ABCA1 or of the ABCA1 mutation carriers were of the LCAT mutation carriers were None of the participants were to for of adrenal were to male controls for In we also included subjects with low HDL-C levels without mutations in ABCA1 or and characteristics of all low HDL-C groups as well as controls are in As HDL-C levels were 39% lower in carriers of ABCA1 or LCAT mutations and in the low HDL-C group, compared with normolipidemic controls < 0.001). levels were lower in carriers of ABCA1 mutations = lower in carriers of LCAT mutations and lower in the low HDL-C = and P = compared with controls. of the of cholesteryl and cholesterol in the total cholesterol and the HDL-C in a of is provided in of male ABCA1 and LCAT mutation carriers and male (n = (n = HDL-C (n = (n = (n = HDL-C (n = is for is for is for is for is for is for is for is for artery disease, is for is for is for is for is for is for is for is for is for is for is for is for mm plasma and urinary cortisol were to plasma and urinary cortisol were to cholesterol, cholesterol, cholesterol, plasma and urinary cortisol were to plasma and urinary cortisol were to plasma and urinary cortisol were to plasma and urinary cortisol were to plasma and urinary cortisol were to plasma and urinary cortisol were to pressure were available in ABCA1 mutation carriers and 17 controls and in LCAT mutation carriers and controls. Plasma ACTH levels were available in ABCA1 mutation carriers and controls and in LCAT mutation carriers and controls. Urinary cortisol levels were available in ABCA1 mutation carriers and controls and in LCAT mutation carriers and controls. are was for history of artery disease was between the two control P is for not P is for plasma and urinary cortisol were to in a cholesterol and cholesteryl ester in a of LCAT mutation carriers and (n = carriers (n = carriers (n = cholesterol, after is for compared with controls. cholesteryl in a Blood pressure were available in ABCA1 mutation carriers and 17 controls and in LCAT mutation carriers and controls. Plasma ACTH levels were available in ABCA1 mutation carriers and controls and in LCAT mutation carriers and controls. Urinary cortisol levels were available in ABCA1 mutation carriers and controls and in LCAT mutation carriers and controls. are was for history of artery disease was between the two control P is for not P is for compared with controls. cholesteryl with was more LCAT mutation carriers = use was more in the ABCA1 and LCAT mutation carriers compared with the control The low HDL-C characteristics compared with the ABCA1 and LCAT with the control group, we lower 24 h urinary excretion of in carriers of mutations in ABCA1 P = in LCAT P = and in the low HDL-C P = and P = These differences after for differences in plasma and use using a = and P = for carriers of ABCA1 mutations or LCAT mutations The steroid excretion of h in the ABCA1 mutation carriers was below the for in the T.J. Schmidt N.A. A.J. van de Calseyde J.F. for 1989; PubMed Scopus Google Scholar). The lower levels of urinary in both ABCA1 and LCAT mutation as well as the low HDL-C group, did not = and P = The of steroid metabolites is in B. was the two heterozygous ABCA1 mutation carriers or the homozygous LCAT mutation carriers to heterozygous Free urinary cortisol was not between ABCA1 mutation carriers and controls P = or LCAT mutation carriers and controls P = Plasma levels of ACTH did not between ABCA1 mutation carriers and controls P = or LCAT mutation carriers and controls P = In a stimulation the cortisol response to levels of ACTH was measured as an to adrenal cortical function I. K. between cortisol and basal for the adrenocorticotropic hormone stimulation PubMed Scopus Google Scholar, The low adrenocorticotropin stimulation in the of patients with adrenal Clin. Endocrinol. Metab. 1998; PubMed Scopus Google Scholar). The serum cortisol response to ACTH was in ABCA1 and LCAT mutation carriers and did not from controls = and P = plasma levels of differences in levels (16Vergeer M. Korporaal S.J. Franssen R. Meurs I. Out R. Hovingh G.K. Hoekstra M. Sierts J.A. Dallinga-Thie G.M. Motazacker M.M. et al.Genetic variant of the scavenger receptor BI in humans.N. Engl. J. Med. 2011; 364: 136-145Crossref PubMed Scopus (266) Google Scholar), were not Plasma levels did not before and after not The study that under normal male individuals with low levels of HDL-C, irrespective of molecular have lower urinary excretion of total compared with normolipidemic indicative of basal corticosteroid A in excretion in both groups did not which a adrenal pathway for HDL steroidogenesis. in either ABCA1 or LCAT did affect the response to and a for of adrenal insufficiency (16Vergeer M. Korporaal S.J. Franssen R. Meurs I. Out R. Hovingh G.K. Hoekstra M. Sierts J.A. Dallinga-Thie G.M. Motazacker M.M. et al.Genetic variant of the scavenger receptor BI in humans.N. Engl. J. Med. 2011; 364: 136-145Crossref PubMed Scopus (266) Google Scholar) did not reveal of adrenal These findings are in with in and that the of plasma lipoprotein-derived cholesterol is used for basal adrenal but that this pathway is not to to stress R. R. of cholesteryl in rat adrenal Lipid Res. Full Text PDF PubMed Google Scholar, S. Chen Y.D. Reaven G.M. of lipoprotein and role of lipoprotein and cholesterol during of response in rat 1983; Full Text PDF PubMed Google M. M. F. of cells in evidence for the of 33: PubMed Scopus Google Scholar). For a adrenal cortisol are upon are of cortisol is to via uptake of cholesterol from We previously reported that individuals with reduced SRB1 function adrenal insufficiency in to a reduced urinary excretion of steroid hormones (16Vergeer M. Korporaal S.J. Franssen R. Meurs I. Out R. Hovingh G.K. Hoekstra M. Sierts J.A. Dallinga-Thie G.M. Motazacker M.M. et al.Genetic variant of the scavenger receptor BI in humans.N. Engl. J. Med. 2011; 364: 136-145Crossref PubMed Scopus (266) Google Scholar). reduced SRB1 function on adrenal cells has a on adrenal steroidogenesis compared with low levels of plasma HDL-C by reduced ABCA1 or LCAT were differences in urinary excretion of in the lower the quantification of cortisol has been shown to be reliable as compared with the quantification of urinary steroid metabolites in the of K. of adrenal the Clin. Full Text Full Text PDF PubMed Scopus Google Scholar, D. J.S. R. R.B. and function of the in 1984; PubMed Scopus Google Scholar). In with of cholesteryl ester is lower in LCAT mutation with the in homozygous adrenal steroidogenesis was not in homozygous carriers compared with heterozygous there is that the adrenal gland has a for cholesteryl as a substrate for steroidogenesis. is by the that a in steroid metabolites was in subjects with low HDL-C not to in Plasma levels of ACTH did not between the low HDL-C and controls. The the that the in urinary steroid metabolites is only a ACTH In line, of the study participants reported of We would to of adrenal cells ABCA1 A. A. R. Zhang E. et and and levels of Invest. 2002; PubMed Scopus Google Scholar). reduced adrenal ABCA1 to of cholesterol in adrenal cells, and steroidogenesis due to cholesterol as for in individuals ABCA1 mutations J.K. Z. B. J.S. et ABCA1 and response to Med. PubMed Scopus Google Scholar, M. J. J.K. Kastelein J.J. Stroes E.S. of mutations in ABCA1 display 2010; 33: PubMed Scopus Google Scholar). Although we this mutations in LCAT as well as low HDL-C in individuals are associated with in HDL-C and urinary steroid an A is that carriers of ABCA1 mutations showed lower levels of plasma levels in to low levels of HDL-C. that low levels of HDL-C and for the but as a role for in adrenal production is (4Illingworth D.R. Lees A.M. Lees R.S. Adrenal cortical function in homozygous familial hypercholesterolemia.Metabolism. 1983; 32: 1045-1052Abstract Full Text PDF PubMed Scopus (49) Google Scholar, 5Illingworth D.R. Alam N.A. Lindsey S. Adrenocortical response to adrenocorticotropin in heterozygous familial hypercholesterolemia.J. Clin. Endocrinol. Metab. 1984; 58: 206-211Crossref PubMed Scopus (21) Google D.R. Kenny T.A. Orwoll E.S. Adrenal function in heterozygous and homozygous hypobetalipoproteinemia.J. Clin. Endocrinol. Metab. 1982; 54: 27-33Crossref PubMed Scopus (70) Google Scholar). In line, for the in did not affect in the urinary steroid the were in carriers compared with controls. are metabolites from the this the use of cholesterol in adrenal steroidogenesis. studies are to and to cholesterol contributes to steroidogenesis in either adrenal or steroid In conclusion, we that basal adrenal steroidogenesis is compromised in males with low levels of plasma HDL-C, a role for cholesterol in adrenal steroidogenesis in humans. The would to C. A. M. and J. F. Los for in the and J. Peter for in the identification of ABCA1 and LCAT mutations. ATP binding cassette transporter A1 adrenocorticotropic hormone cortisol binding HDL cholesterol 17 ketogenic steroid metabolites LDL cholesterol 17 hydroxycorticosteroids scavenger receptor type B1