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Endocrinology Vol. 143, No. 5 1809-1816
Copyright © 2002 by The Endocrine Society

RECEPTORS

Prolonged Stimulation of the Adrenals by Corticotropin Suppresses Hepatic Low-Density Lipoprotein and High-Density Lipoprotein Receptors and Increases Plasma Cholesterol

Cecilia Gälman, Bo Angelin and Mats Rudling

Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institute at Huddinge University Hospital, 141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Mats Rudling, Center for Metabolism and Endocrinology, M63, Huddinge University Hospital, Karolinska Institute, 141 86 Huddinge, Sweden. E-mail: . mats.rudling{at}cnt.ki.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pituitary ACTH has been shown to strongly stimulate adrenal receptors for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) scavenger receptor class B type 1(SR-BI) to provide precursor cholesterol for glucocorticoid synthesis. The present study aimed to determine the effects of ACTH on hepatic cholesterol metabolism and plasma lipoproteins. Treatment of Sprague Dawley rats or normal C57BL/6J mice with ACTH for 3.5 d reduced hepatic SR-BI and LDL receptors. Simultaneously, cholesterol in plasma LDL and HDL was increased. None of these effects could be reproduced using glucocorticoids instead of ACTH, and they were abolished in adrenalectomized rats, indicating an obligate role of the adrenals for the effects of ACTH observed in the liver. When ACTH was given to LDL receptor-deficient mice, plasma LDL did not increase and the increase in HDL cholesterol remained, as did the suppression of hepatic SR-BI. Our data show that prolonged ACTH treatment suppresses hepatic SR-BI and LDL receptors in vivo in rodents, resulting in elevated plasma HDL and LDL. The adrenals are obligate for these effects, suggesting that ACTH releases some factor(s) that suppresses hepatic LDL and SR-BI receptors. Hypothetically, this novel mechanism would further promote channeling of cholesterol to the adrenals in situations of prolonged stress.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CHOLESTEROL CONSTITUTES A component of extra- and intracellular membranes and is needed to maintain normal cell growth and multiplication (1, 2). It is the precursor of steroid hormones and bile acids and a structural component of lipoprotein particles involved in the transport of lipid energy to the tissues (2). Cells may acquire cholesterol by de novo synthesis or from circulating lipoproteins. Through sterol-sensitive release of membrane-bound transcription factors, each cell regulates its cholesterol homeostasis (3). Binding, uptake, and degradation of lipoprotein cholesterol is to a large extent regulated by the expression of cell-surface low-density lipoprotein (LDL) receptors (LDLRs), which is under transcriptional control by cholesterol (1, 3). Other members of the LDLR gene family, such as the LDLR-related protein and the very low-density lipoprotein (VLDL) receptor, may be involved in the cellular uptake of lipoprotein cholesterol (4, 5). The recently described high-density lipoprotein (HDL) receptor, scavenger receptor class B type I (SR-BI), can facilitate the specific uptake of cholesteryl esters into the cell without significant degradation of the HDL apolipoproteins (6, 7, 8). SR-BI is also believed to be involved in the export of cholesterol from peripheral tissues (9).

Elevated levels of plasma LDL cholesterol are associated with an increased risk of atherosclerosis, whereas high levels of HDL cholesterol exert a protective effect (10, 11, 12). Regulation of hepatic LDLRs is an important determinant of plasma LDL cholesterol concentrations (2, 13, 14), and recent observations in rodents indicate that modulation of hepatic HDL receptor expression is important for the HDL cholesterol level (15, 16, 17, 18, 19, 20). Whereas liver LDLRs to a large extent are regulated by the demand for cholesterol in the hepatocyte (2, 13), little is known about the physiological regulation of SR-BI in the liver (9).

Certain hormones also have a powerful influence on lipoprotein receptor expression (21, 22, 23, 24). Such mechanisms are important in steroid hormone-producing tissues, such as the adrenal glands, ovaries, and testes (9, 25, 26, 27, 28). It is well known that adrenal steroid hormones are largely derived from lipoprotein cholesterol (29, 30, 31) and that several uptake mechanisms are involved (32, 33). In response to pituitary ACTH, there is a rapid and strong induction of both LDL and SR-BI receptors (21, 28, 34, 35, 36, 37).

An intact pituitary function is also necessary to maintain normal hepatic cholesterol metabolism (38). Accordingly, hypophysectomy is associated with drastic changes in cholesterol and lipoprotein metabolism (38, 39). Pituitary TSH appears to affect hepatic cholesterol metabolism via T4 (40, 41, 42), whereas GH has direct effects on the liver (43). However, even in combination with T4 and corticosteroids, GH substitution cannot completely revert the dyslipoproteinemia in hypophysectomized rats (39). In human studies, administration of ACTH, but not of glucocorticoids, has been reported to reduce LDL and increase HDL, presumably through direct stimulation of hepatic LDLRs (44, 45).

Against this background, we decided to characterize in vivo the effects of ACTH on lipoprotein receptor expression in rat liver. Unexpectedly, we found that although treatment with ACTH for more than 2 d strongly induced both LDLR and SR-BI expression in the adrenals, both receptors were concomitantly suppressed in the liver, resulting in increased plasma LDL and HDL levels. These effects could not be reproduced by glucocorticoids and were abolished in adrenalectomized (Adx) animals given ACTH. Our data indicate that in response to prolonged ACTH stimulation, the adrenals may secrete a factor that down-regulates receptors responsible for hepatic LDL and HDL cholesterol uptake.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Altogether, 124 male Sprague Dawley rats (7–8 wk old, weighing 250–300 g) and 16 C57BL/6J and 16 LDLR-negative (LDLR-/-) male mice (5–6 wk) were used (46). Adrenalectomized (Adx) male rats and their controls were from A/S Mollegaard (Skensved, Denmark); all other rats were from B&K Universal AB (Sollentuna, Sweden). Mice were from M&B (Ry, Denmark). All studies were approved by the institutional Animal Care and Use Committee.

Experimental set-up
All animals had free access to water and chow. Light-cycle hours were from 0600 h to 1800 h. All Adx rats were substituted with hydrocortisone sc twice daily (400 µg/kg per day) and 0.9% NaCl as drinking water. Rats received 2% dietary cholesterol (39) for 8 d; on d 5 ACTH treatment was initiated. Tetracosactide (ACTH) (Synacthen depot, Ciba-Geigy, Horsham, Sussex, UK), hydrocortisone (Solu-cortef; Upjohn, Puurs, Belgium), or 0.9% NaCl (controls) was injected sc at 0900 h and 1600 h for 3.5 d. Animals were anesthetized, bled by cardiac puncture, and killed by cervical dislocation. Plasma was separated and stored at +4 C. Livers and adrenals were frozen in liquid nitrogen and stored at -85 C.

Separation of lipoproteins by fast protein liquid chromatography (FPLC)
Lipoproteins from pooled plasma samples (6 ml) were separated by ultracentrifugation at density 1.21 g/ml. The lipoproteins (1 ml) were then separated by FPLC after volume adjustment (22, 47). In the experiment in Fig. 6Go, FPLC was performed on 10 µl of plasma, using a miniaturized on-line system (41).



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  		Figure 6. Effect of ACTH on C57BL/6J wild-type mice (wt) and LDLR-deficient mice. Groups of mice (seven wt and eight LDLR-/- mice) received ACTH (500 µg/kg per day) or NaCl, control groups (nine wt and eight LDLR-/- mice) for 3.5 d. A, Total plasma cholesterol. Means and SEM are shown. B, Plasma lipoprotein profile after separation by miniaturized FPLC. NaCl-treated C57BL/6J wt mice (black line) ACTH-treated C57BL/6J wt mice (blue line), NaCl-treated LDLR-/- mice (red line) and ACTH-treated LDLR-/- mice (green line). C, Hepatic LDLR (~120 kDa) expression assayed by ligand blot. Two lanes were run for each group (150 µg and 300 µg protein, respectively), n.d., Not detectable. D, Expression of hepatic SR-BI (~80 kDa) assayed by immunoblot. Three lanes were run for each group (25, 50, and 100 µg protein, respectively). Quant, Quantitation of the binding activity in arbitrary units; n.q., not quantified.

 
Cholesterol assay
Cholesterol in plasma and FPLC fractions was assayed with a commercial kit (Roche Diagnostics GmbH, Mannheim, Germany).

Assay of 7{alpha}-hydroxy-4-cholesten-3-one (C4)
Plasma (500 µl) was diluted with saline and 7ß-hydroxy-4-cholesten-3-one was added as internal standard (48). The samples were extracted on C8 Isolute SPE columns (500 mg and 3 ml, International Sorbent Technology Ltd., Hengoed, UK) essentially as described (49). The eluted product was dried under N2 and dissolved in 100 µl acetonitrile (HPLC grade, Merck, Darmstadt, Germany), and 50 µl were separated by HPLC (HP 1100 series, Hewlett-Packard Co. GmbH, Waldbronn, Germany) at 20 C (mobile phase: acetonitrile/water 95/5, 1 ml/min) using a Nova-Pak C18 steel column 3.9 x 300 mm inner diameter, 4 µm particle size (Waters Corp., Milford MA). The wavelength was 241 nm.

Ligand blot assay of LDL receptors
Membranes from livers and adrenals were prepared as described (23). The indicated amounts of membrane proteins prepared from pools of tissue from all animals in each group or from each animal were separated on a 6% SDS-polyacrylamide gel under nonreduced conditions. Size markers (high-molecular-weight standards, Bio-Rad Laboratories, Inc., Hercules, CA) were reduced with 2-mercaptoethanol (4%) and boiled for 5 min before loading. The samples were electrophoresed and transferred onto nitrocellulose filters that were incubated with 125I-labeled rabbit ß-VLDL (23). The membranes were dried and exposed on x-ray film at -70 C. The LDLR bands (~120 kDa) were analyzed using a Bio-Imaging BAS 1800 analyzer (Fuji Photo Film Co., Ltd., Tokyo, Japan). Quantitation of data was performed with Image Gauge software (Science Lab 98 version 3.12, Fuji Photo Film Co., Ltd.). The measured bands were expressed in arbitrary units after subtraction of background.

Immunoblot of SR-BI
Indicated amounts of membrane proteins and size markers (high-molecular-weight standards, Bio-Rad Laboratories, Inc.) were added to Laemmli sample buffer (Bio-Rad Laboratories, Inc.), reduced with 2-mercaptoethanol (4%), and separated on 7.5% or 4–20% Criterion Tris-HCl gels (Bio-Rad Laboratories, Inc.) using a Criterion cell at 200 V for 1 h. The separated proteins were transferred onto 0.45-µm nitrocellulose filters (Criterion blotting sandwiches) with a Criterion blotter at 100 V for 30 min. The membrane was blocked for 2 h (5% nonfat dried milk in Tris-buffered saline [TBS] containing 0.01% Tween 20), incubated overnight with rabbit polyclonal antibodies raised against mouse SR-BI (1:1500) (Novus Biologicals, Inc., Littleton, CO), washed 1 x 15 min and 2 x 5 min with TBS containing 0.01% Tween 20, incubated with peroxidase conjugated sheep antirabbit Ig (1:10,000) for 2 h (The Binding Site Ltd., Birmingham, UK). Filters were washed (1 x 15 min and 4 x 5 min) with TBS containing 0.01% Tween 20. Chemiluminescence substrate was added (Supersignal, Pierce Chemical Co., Rockford, IL). In all experiments except Fig. 7AGo, the filters were exposed on x-ray film at room temperature. Chemiluminescence was determined with an LAS 1000 plus luminescent imager analyzer (Fuji Photo Film Co., Ltd.). The blot in Fig. 7AGo was directly generated in the LAS 1000 plus imager. Quantitation of data was performed with Image Gauge software (Science Lab 98 version 3.12, Fuji Photo Film Co., Ltd.).



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  		Figure 7. A, Effect of ACTH on the expression of hepatic SR-BI in intact and Adx rats (see legend to Fig. 5Go); this blot was generated in the LAS 1000 imager analyzer. Two lanes were run for each group (75 and 150 µg protein, respectively). B, Time course for ACTH effects on expression of SR-BI in the liver (see legend to Fig. 2Go). Two lanes were run for each group (100 and 200 µg protein, respectively). C, Effect of hydrocortisone on hepatic SR-BI expression (see legend to Fig. 4Go). Two lanes were run for each group (100 and 200 µg protein, respectively). D, Effect of ACTH on the expression of SR-BI in the adrenals (see legend to Fig. 1Go). Two lanes were run for each group (75 and 150 µg protein, respectively). The expression of SR-BI (~80 kDa) was assayed by immunoblot as described in Materials and Methods. Quant, Quantitation of the binding activity in arbitrary units.

 
Preparation of hepatic RNA
Samples were homogenized with a Kinematica Polytron (Kriens, Lucerne, Switzerland) at 4 C. RNA was isolated using QuickPrep total RNA extraction kit (Amersham Pharmacia Biotech Inc., Piscataway, NJ). The RNA was quantitated assuming 1 A260 unit = 40 µg RNA/ml.

Solution hybridization assay
LDLR mRNA was measured by a solution hybridization assay using cRNA probes (50).

Statistics
Data are presented as means ± SEM. Difference between groups was tested by one-way ANOVA followed by comparison of group means according to Dunnet’s test if not stated otherwise. Two-way ANOVA was used for the experiments in Figs. 3Go, 5Go, and 6Go, followed by comparison of group means according to LSD test (Statistica software, Stat Soft, Tulsa, OK).



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  		Figure 3. Effect of ACTH on the sensitivity to dietary cholesterol. Two groups of rats (five animals/group) received 2% dietary cholesterol for 8 d; the other two groups received regular chow. On d 4, ACTH treatment (500 µg/kg per day) for 3.5 d was initiated. A, Total plasma cholesterol (open bars), plasma concentration of C4 (black bars). Mean and SEM are shown. B, Cholesterol content in lipoproteins after separation of pooled plasma by FPLC. NaCl regular chow (open circles), ACTH regular chow (filled circles), NaCl 2% cholesterol diet (open squares), and ACTH 2% cholesterol diet (filled squares). C, Hepatic LDLR (~120 kDa) expression assayed by ligand blot. Two lanes were run for each group (150 µg and 300 µg protein, respectively). Quant, Quantitation of the binding activity in arbitrary units. LDLR mRNA levels were quantified in each individual by solution hybridization as described in Materials and Methods. Mean and SEM are shown.

 


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  		Figure 5. Effect of ACTH on intact and Adx rats. Groups of six rats received injections of ACTH (500 µg/kg per day) or NaCl (controls) for 3.5 d. A, Total plasma cholesterol. Mean and SEM are shown. B, Cholesterol content in lipoproteins after separation of pooled plasma by FPLC. NaCl intact (open circles), ACTH intact (filled circles), NaCl Adx (open squares), and ACTH Adx (filled squares). C, Hepatic LDLR (~120 kDa) expression assayed by ligand blot. One lane was run for each animal (300 µg were loaded). Quant, Quantitation of the binding activity in arbitrary units. LDLR mRNA levels were quantified in each individual by solution hybridization as described in Materials and Methods. Mean and SEM are shown.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In the first experiment, we wanted to determine the effects of ACTH on the expression of hepatic LDLRs. Rats were injected subcutaneously twice daily for 3.5 d with ACTH at two doses (100 µg/kg per day or 500 µg/kg per day) or with saline (controls) (Fig. 1Go). As expected (21, 34, 35, 36), this treatment resulted in a strong dose-dependent stimulation of adrenal LDLRs (Fig. 1AGo). However, the LDLR expression in liver membranes was simultaneously reduced by more than 50% following the high dose of ACTH (Fig. 1BGo). The entire ligand blot was repeated four times with the same result. LDLR expression was also analyzed in liver membranes from all 18 individual animals and was significantly reduced (25 ± 2.0 vs. 37± 1.4 arbitrary units) in the group receiving a high dose of ACTH (Mann-Whitney test P < 0.01 vs. controls). In accordance with this suppression of hepatic LDLRs, total plasma cholesterol was increased by about 60% (P < 0.01) at the high dose of ACTH (Fig. 1CGo). To analyze plasma lipoproteins in detail, pools of plasma were separated by FPLC, and fractions were assayed for cholesterol. The lipoprotein profiles showed that the increase in cholesterol was within LDL and large HDL particles (Fig. 1DGo).



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  		Figure 1. Effect of ACTH treatment on hepatic and adrenal LDLRs and plasma cholesterol. Rats (six animals/group) received sc injections of ACTH (100 and 500 µg/kg per day) for 3.5 d. A, LDLR (~120 kDa) expression in adrenals and (B) liver assayed and quantitated by ligand blot as described in Materials and Methods. Two lanes were run for each group (100 µg and 200 µg protein, respectively). Quant, Quantitation of the binding activity in arbitrary units. C, Total plasma cholesterol from individual plasma samples. Mean and SEM are shown. D, Cholesterol content in lipoproteins after separation of pooled plasma by FPLC. NaCl-treated controls (open circles), ACTH 100 µg/kg per day (open triangles), ACTH 500 µg/kg per day (filled circles).

 
We then determined the time course for the effects of ACTH. Rats were injected with ACTH (twice daily, 500 µg ACTH/kg per day), and groups of animals were killed 3, 20, 44, and 75 h after the first injection (Fig. 2Go). Analysis of hepatic LDLR expression revealed that suppression of receptors did not occur until after 44 h (more than four injections) (Fig. 2BGo). Assay of the LDLR expression in all individual animals revealed a significant decrease (26 ± 4.8 vs. 52 ± 7.4 arbitrary units) in the group receiving ACTH for 75 h (Dunnett’s test P < 0.05 vs. control). Also, plasma total cholesterol was increased first after 44 h of treatment (Fig. 2AGo), and the lipoprotein profiles of pooled plasma confirmed this finding (Fig. 2CGo).



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  		Figure 2. Time course for ACTH effects. Groups of four rats were injected twice daily with ACTH (500 µg/kg per day) and killed 3, 20, 44, and 75 h after injection start. The experiment was staggered so that all animals were killed at the same occasion. One group of animals was injected with saline twice daily (NaCl) for 75 h. A, Total plasma cholesterol. Mean and SEM are shown. B, Hepatic LDLR (~120 kDa) expression assayed by ligand blot. Two lanes were run for each group (100 µg and 200 µg protein, respectively). Quant, Quantitation of the binding activity in arbitrary units. C, Cholesterol content in lipoproteins after separation of pooled plasma by FPLC as described in Materials and Methods. Saline-injected (open circles) groups killed 3 (open squares), 20 (filled squares), 44 (filled circles), and 75 (filled triangles) h after treatment start.

 
Our finding that ACTH strongly reduces hepatic LDLRs suggested that this hormone may also modulate the sensitivity to dietary cholesterol in these animals. To evaluate this, groups of rats received 2% dietary cholesterol or regular chow and were treated with ACTH (500 µg/kg per day) or saline for 3.5 d (Fig. 3Go). Cholesterol feeding did not significantly increase total plasma cholesterol levels. However, in agreement with previous findings (39), FPLC profiles showed that the distribution of cholesterol in plasma was shifted into larger particles, whereas cholesterol in small particles was reduced, compared with animals on regular chow. ACTH treatment increased total plasma cholesterol in rats receiving cholesterol and in rats on normal chow (two-way ANOVA, P < 0.001) (Fig. 3AGo), and this was owing to an increase mainly in HDL cholesterol in both situations (Fig. 3BGo).

In line with previous results (39), cholesterol feeding induced hepatic LDLRs (Fig. 3CGo). ACTH treatment reduced hepatic LDLR expression in both chow-fed and cholesterol-fed animals, compared with controls. The level of LDLR mRNA, assayed by solution hybridization, decreased following cholesterol feeding but was not influenced by ACTH treatment (Fig. 3CGo). Thus, although ACTH treatment clearly reduced hepatic LDLR expression, this did not make the animals more sensitive to dietary cholesterol. Also in this model, ACTH increased HDL cholesterol.

Feeding rats with cholesterol induces the conversion of cholesterol into bile acids in the liver (51, 52). To evaluate whether ACTH also influenced this pathway of cholesterol conversion, we measured the concentration of C4, a plasma marker that reflects the rate of bile acid production (49). Cholesterol feeding increased the C4 level by 100% in both NaCl- and ACTH-treated animals (two-way ANOVA P < 0.01) (Fig. 3AGo). ACTH-treatment significantly reduced the C4 level both in normal and cholesterol-fed animals by 40% and 30%, respectively (two-way ANOVA P < 0.05), indicating that bile acid synthesis was reduced in response to hormone treatment in both situations.

A major physiological effect of ACTH is to increase adrenal glucocorticoid secretion. We therefore wanted to know whether glucocorticoids could reproduce the effects of ACTH administration. Animals were injected twice daily with hydrocortisone at a physiological (400 µg/kg per day) and at a pharmacological (100 mg/kg per day) dose (Fig. 4Go). Hydrocortisone did not significantly alter plasma cholesterol at any dose (Fig. 4AGo). Analysis of the plasma lipoprotein pattern confirmed this finding; if anything, a slight reduction in LDL and large HDL fractions was seen in samples from animals treated with the high dose (Fig. 4BGo). Assay of hepatic LDLRs showed that hydrocortisone did not alter receptor expression (Fig. 4CGo).



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  		Figure 4. Effect of glucocorticoids on hepatic LDLRs and plasma cholesterol. Animals (six rats/group) were injected twice daily for 3.5 d with hydrocortisone at a physiological (400 µg/kg per day) and pharmacological (100 mg/kg per day) dose. A, Total plasma cholesterol. Mean and SEM are shown. B, Cholesterol content in lipoproteins after separation of pooled plasma by FPLC. NaCl (open circles), hydrocortisone 400 µg/kg per day (filled squares), hydrocortisone 100 mg/kg per day (filled circles). C, Hepatic LDLR (~120 kDa) expression assayed by ligand blot as described in Materials and Methods. Two lanes were run for each group (150 µg and 300 µg protein, respectively). Quant, Quantitation of the binding activity in arbitrary units.

 
Effects of glucocorticoids can, however, be somewhat complicated to interpret because previous studies have shown that they can exert biphasic effects in some tissues (53, 54). We therefore determined the effects of hydrocortisone over a wide dose range. In a separate experiment, rats were injected twice daily with increasing doses of hydrocortisone (50 µg/kg per day, 150 µg/kg per day, 400 µg/kg per day, 4 mg/kg per day, and 100 mg/kg per day or saline, controls). There was no effect of these treatments on total plasma cholesterol or the lipoprotein pattern in any of the groups (data not shown).

Because hydrocortisone could not reproduce the effects observed in response to ACTH, we wanted to determine whether the presence of adrenals was important for the ACTH-induced suppression of hepatic LDLRs. For this purpose, normal and Adx rats were treated with ACTH or saline for 3.5 d (Fig. 5Go). All Adx rats received glucocorticoid substitution (400 µg hydrocortisone/kg per day) twice daily. Injection of ACTH to Adx rats did not increase total plasma cholesterol, whereas an increase was detected in intact rats treated with ACTH (Fig. 5AGo). Assay of the lipoprotein profiles confirmed the lack of effect of ACTH in Adx rats. Thus, the ACTH-induced increases in LDL and large HDL cholesterol in intact rats were absent in Adx animals (Fig. 5BGo).

Analysis of LDLR expression in liver membranes from all individual animals showed that the strong ACTH-induced suppression of LDLRs observed in intact rats (Mann-Whitney test P < 0.05) was not present in Adx rats (Fig. 5CGo). Thus, the ACTH-induced suppression of hepatic LDLRs in the rat requires intact adrenals. Quantitation of LDLR mRNA levels by solution hybridization again showed that ACTH treatment did not alter the LDLR mRNA levels in intact or in Adx rats (Fig. 5CGo).

We then asked whether the ACTH-induced suppression of hepatic LDLRs was responsible for the concomitant increases in plasma of both LDL and HDL cholesterol. For this purpose, LDLR-deficient mice (46) and their wild-type controls, C57BL/6J mice, were treated with ACTH twice daily for 3.5 d at a dose of 500 µg/kg per day (Fig. 6Go). ACTH treatment of wild-type mice had the same effects as previously established in rats: plasma cholesterol increased, mainly in LDL and HDL (Fig. 6Go, A and B). However, in LDLR deficient mice treated with ACTH, total plasma cholesterol did not increase. Analyses of the lipoprotein patterns showed that the increase in LDL cholesterol was absent in LDLR-deficient mice; if anything a reduction was obtained (Fig. 6BGo). However, the ACTH-induced increase in HDL was still present in these animals.

The finding that ACTH treatment increased plasma HDL cholesterol in a situation in which LDLRs are absent suggested that ACTH might also regulate structures of importance in HDL metabolism. We therefore assayed the protein expression of the HDL receptor, SR-BI, because recent studies indicate that the hepatic expression of this structure may have an important role in regulating plasma HDL cholesterol levels (9). Western blot analysis showed that hepatic SR-BI expression was increased in LDLR-deficient mice, compared with wild-type controls (Fig. 6DGo). Treatment with ACTH suppressed the expression of SR-BI in both normal and knockout mice by 50%. This blot was repeated with the same result.

The finding that ACTH reduced the hepatic expression of SR-BI in mice prompted us to investigate whether this suppression was also present in the rat and whether the presence of the adrenals was important. To study this, we analyzed SR-BI expression in the liver membranes from the previous experiment described in Fig. 5Go. Western blot analysis demonstrated that ACTH treatment reduced SR-BI expression by about 50% in intact rats. This suppression was abolished in Adx rats, in which the expression instead was increased (Fig. 7AGo). We then determined the effect of ACTH on SR-BI expression in the livers from the time course experiment described in Fig. 2Go. As for the LDLR, there was no suppression of SR-BI until after 44 h (more than four injections) (Fig. 7BGo). To statistically confirm this finding, we also assayed the SR-BI expression using liver membranes prepared from all 20 individual animals of the entire experiment (not shown). ACTH significantly suppressed the expression of SR-BI after 44 h of treatment (Dunnett’s test, P < 0.05 vs. controls). To study whether this effect of ACTH on SR-BI could be mediated by glucocorticoids, we analyzed SR-BI expression in liver membranes from the experiment described in Fig. 4Go. Hydrocortisone treatment did not suppress but instead increased SR-BI expression (Fig. 7CGo). As expected, SR-BI expression in the adrenal gland was strongly stimulated by ACTH treatment for 3.5 d (Fig. 7DGo).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The acquisition of lipoprotein cholesterol by the adrenal glands in response to pituitary ACTH is of paramount importance for the animal to cope with external stress. The rapid induction of both LDL and HDL receptors, as well as the increase in cholesterol synthesis, underlines this important physiological reaction (21, 28, 34, 35, 36, 37). Our results from rats and mice show that both LDL and HDL receptors in the liver are suppressed following ACTH administration. These responses were not observed after hydrocortisone treatment, and they were absent in animals devoid of adrenals. In contrast to the previously described rapid induction (within hours) of both LDL and HDL receptors in the adrenals (21, 28, 34, 35, 36, 37), repeated injections with ACTH for more than 2 d were needed to observe these effects in the liver. The changes in plasma lipoprotein cholesterol were reciprocal to those in hepatic lipoprotein receptor expression, clearly indicating the physiological relevance of the receptor findings.

Taken together, these data strongly indicate that ACTH does not have a direct effect on the liver, a conclusion in concert with the fact that ACTH receptors have not been identified in hepatic tissue (55). Instead, the data are consistent with the hypothesis that prolonged stimulation of the adrenals by ACTH results in the release of one or several factors that suppress hepatic lipoprotein receptors. Because the effects on both LDL and HDL receptors were relatively pronounced and associated with enhanced plasma cholesterol, the identification of this mechanism(s) will obviously be important. The suppression of hepatic LDLRs occurred without any change in LDLR mRNA levels, which may indicate regulation of the posttranscriptional level. Furthermore, the measurements of C4 levels indicate that the effect may at least partially be related to suppressed bile acid synthesis. The adrenals synthesize and secrete many compounds in response to chronic stress, and these compounds may obviously also elicit secondary responses in other tissues. So far, we have not been able to identify any adrenal steroid hormone as responsible (Gälman, C., B. Angelin, M. Axelson, and M. Rudling, unpublished data).

The present data also provide information on the role of hepatic lipoprotein receptors in the regulation of plasma cholesterol levels. The importance of liver LDLR regulation for the plasma LDL cholesterol level is well established, and the increases observed in plasma were of a magnitude in line with the findings of an approximately 50% reduced LDLR expression (56). The role of the HDL receptor SR-BI in the physiological regulation of HDL cholesterol is less well established. However, genetic manipulations resulting in varying degrees of over- or underexpression of this structure in mouse liver indicate that SR-BI can modulate HDL cholesterol (15, 16, 18, 19, 20). Otherwise, the only situations in which SR-BI expression has been reported to be affected are following high-dose estrogen treatment (27) and on the feeding of a diet rich in polyunsaturated fat (57). Our present data lend further support to the concept that plasma HDL cholesterol levels may be under control by regulation of hepatic SR-BI.

Our experiments in mice confirmed that the ACTH-induced suppression of hepatic LDLRs was also present in this species. The observation of a clearly increased expression of hepatic SR-BI in LDLR knockout mice, a model of the human disorder familial hypercholesterolemia (46, 58), has, to our knowledge, not been reported previously. As mentioned, SR-BI is known to be down-regulated in livers of estrogen-treated rats, and it has been suggested that, like the LDLR, SR-BI can respond to cellular cholesterol (26, 27). The up-regulation of SR-BI in LDLR-deficient mice may thus be a compensatory mechanism. The relevance of this finding for patients with familial hypercholesterolemia is not clear. It is of interest to note, however, that HDL cholesterol levels are generally somewhat reduced in patients with this disorder (58).

The LDLR-deficient mice provided an interesting possibility to further study the effect of ACTH on SR-BI and HDL cholesterol. In these animals, the suppression of SR-BI and the increase in HDL persisted, again supporting the concept that modulation of SR-BI can affect plasma lipoproteins. The lack of effect on LDL cholesterol in this model demonstrates the importance of the LDLR for the increase in plasma LDL observed in response to ACTH.

Thus, in both rats and mice, the chronic administration of ACTH results in suppression of hepatic lipoprotein receptors and increases in plasma lipoprotein cholesterol. This could hypothetically be regarded as a physiological response to a situation of chronic stress, which will guarantee a continued access of cholesterol to the adrenals. It is of interest to discuss whether these findings may have any relevance to the situation in humans. In some studies, Berg and Nillson-Ehle (44) and Arnadottir et al. (59) have reported that ACTH administration to normal volunteers for 4 d resulted in a lowering of LDL and an increase in HDL cholesterol in plasma. This discrepancy in LDL cholesterol response is difficult to explain and may indicate a fundamental species difference. However, one other possible explanation may be discussed. Compared with rats and mice, humans have a considerably lower hepatic LDLR expression (Gälman, C., P. Parini, B. Angelin, and M. Rudling, unpublished data), at least partly explaining their much higher LDL cholesterol levels under basal conditions (14). In fact, lipoprotein metabolism in humans may actually more closely resemble that in the LDLR knockout mice, in which indeed plasma LDL levels were reduced in response to ACTH. The explanation for this finding may therefore be related to other effects of ACTH on lipoprotein metabolism, not involving LDLRs. Such mechanisms may include reduced production of LDL precursors, such as VLDL (60). In preliminary experiments in the rat, we have not observed any effects of prolonged ACTH treatment on hepatic lipoprotein triglyceride secretion, as studied by the Triton WR 1339 technique (61), but further studies are needed to evaluate this hypothesis.

In conclusion, we have found evidence of a novel mechanism for the in vivo modulation of hepatic lipoprotein receptors in rodents. The chronic exposure to ACTH results in stimulation of adrenal lipoprotein receptors at the same time as hepatic receptors are suppressed, leading to elevated plasma LDL and HDL cholesterol. Hypothetically, this mechanism would channel cholesterol to maintain a continuous high production of adrenal steroids. The role of such an adaptation for the development of dyslipidemia in situations of chronic stress should be important to study.


   Acknowledgments
 
We thank Mrs. Lilian Larsson and Mrs. Ingela Arvidsson for technical assistance and Dr. Paolo Parini for advice on statistics.


   Footnotes
 
This work was supported by grants from the Swedish Medical Research Council (31X-07137, 32X-14053, 14GX-13571); the Swedish Foundation for Strategic Research; the Grönberg, Ax:son Johnson, Ruth and Richard Julin Foundations; and the Swedish Heart-Lung Foundation; "Förenade Liv" Mutual Group Life Insurance Co.; the Foundation of Old Female Servants; and the Karolinska Institute.

Abbreviations: Adx, Adrenalectomized; C4, 7{alpha}-hydroxy-4-cholesten-3-one; FPLC, fast protein liquid chromatography; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; SR-BI, scavenger receptor class B type I; TBS, Tris-buffered saline; VLDL, very low-density lipoprotein.

Received July 16, 2001.

Accepted for publication January 31, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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