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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2522-2527
Copyright © 1997 by The Endocrine Society

Experimental Studies

Ribonucleic Acid Expression of the CLA-1 Gene, a Human Homolog to Mouse High Density Lipoprotein Receptor SR-BI, in Human Adrenal Tumors and Cultured Adrenal Cells1

Jianqi Liu, Raimo Voutilainen, Päivi Heikkilä and Arvi I. Kahri

Department of Pathology, University of Helsinki (J.L., R.V., P.H., A.I.K.), FIN-00014 Helsinki; and the Department of Pediatrics, Kuopio University Hospital (R.V.), FIN-70210 Kuopio, Finland

Address all correspondence and requests for reprints to: Dr. Jianqi Liu, Department of Pathology, P.O. Box 21, University of Helsinki, FIN-00014 Helsinki, Finland. E-mail: Jiangi.Liu{at}helsinki.fi


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Human CLA-1 is homologous to the mouse SR-BI gene, which was recently identified as a high density lipoprotein receptor involved in selective cholesterol uptake in rodent adrenal cells. We screened 42 normal and pathological adrenal samples by Northern blotting and found abundant expression of CLA-1 messenger ribonucleic acid (mRNA) in normal adult and fetal adrenals, adrenocortical adenomas, and hyperplasias. Adrenocortical carcinomas and the adrenals adjacent to Cushing’s adenomas contained less CLA-1 mRNA than normal adrenals. CLA-1 mRNA was also highly expressed in a Leydig cell tumor, but much less in liver, kidney, and pheochromocytomas. The accumulation of CLA-1 mRNA in primary cultures of normal adrenocortical cells was up-regulated by ACTH in a dose- and time-dependent manner. Both dibutyryl cAMP and staurosporine increased the basal expression of CLA-1 mRNA. Although there was no additive effect of ACTH and dibutyryl cAMP, staurosporine slightly enhanced the stimulatory effect of ACTH on the expression of CLA-1 mRNA. The abundant expression of CLA-1 mRNA and its regulation by the physiological hormone ACTH in human adrenal cells suggest that CLA-1 has a role in adrenal steroidogenesis, probably as a lipoprotein receptor mediating the selective cholesterol uptake in these cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SR-BI (SCAVENGER receptor, class B, type I) was first cloned from a Chinese hamster ovary cell variant as a new member of the CD36 gene family of membrane proteins and displayed high affinity binding for acetylated and native low density lipoprotein (LDL) (1). Recently, it was identified as a high density lipoprotein (HDL) receptor mediating the selective cholesterol uptake without degradation of the protein component of HDL in mouse (2). SR-BI protein is abundant in nonplacental steroidogenic tissues and liver (2), the tissues actively involved in selective uptake of cholesterol from HDL (3). The adrenal glands are the richest source of SR-BI messenger ribonucleic acid (mRNA) and protein in vivo in both rats (4) and mice (2, 5). This expression is up-regulated in response to depletion of cholesterol stores, whether resulting from decreased availability of cholesterol (reduction of HDL cholesterol in vivo) or increased cholesterol utilization for corticosteroid synthesis (treatment with ACTH in vitro). It was suggested that this feedback loop controls SR-BI expression and thereby helps to maintain cholesterol stores and corticosteroid biosynthesis in rodent adrenals (5).

The quantitative significance of selective HDL cholesterol uptake may depend on the species examined. In mice it accounts for 90% or more of the cholesterol destined for steroid production or cholesteryl ester accumulation in steroidogenic cells (6, 7). However, the LDL receptor, rather than the HDL receptor, has been proposed to be the major gateway of cholesterol uptake to satisfy the very high cholesterol requirements of human fetal adrenal cells (8). Adequate concentrations of LDL, not HDL, could suppress 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in endogenous cholesterol synthesis, in human fetal adrenal cells (9). Furthermore, the plasma cholesterol pool in the human fetus is believed to be regulated at least in part by the rate of LDL cholesterol uptake and utilization by the fetal adrenals as a substrate for steroidogenesis (10). The role of HDL receptor-mediated selective cholesterol uptake in human adrenals remains to be established.

Human CLA-1 (CD36 and LIMPII Analogous-1) was identified as a member of the CD36 gene family and is widely expressed (11). Human CLA-1 and mouse SR-BI are highly homologous (79% amino acid sequence identity), and they probably represent the same gene in different species (2, 11). We now provide evidence that the human CLA-1 gene is highly expressed in human adrenals in vivo, and its mRNA accumulation is up-regulated by ACTH treatment through the cAMP-dependent protein kinase pathway in vitro.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues

Normal adrenals were obtained from four patients who underwent nephrectomy for kidney tumors. Pathological adrenal glands were obtained during the operations performed at the Department of Surgery, Helsinki University Central Hospital. The pathological adrenal tissues investigated in this study are listed in Table 1Go. Human fetal adrenals, a Leydig cell tumor, and normal liver and kidney tissues were used for comparison. Tissue processing and histological diagnostics were described previously (12).


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  		Table 1. Relative levels of CLA-1 mRNA in adrenal tumors and control tissue

 
Cell cultures

Small pieces of normal and pathological tissues were briefly frozen in liquid nitrogen and then stored at -70 C. The remaining tissues were prepared for primary cultures and treated as described previously (12). The medium used in the treatment phase was serum free. The test agents were added as single doses. All experiments were performed in triplicate wells and repeated at least twice with tissues from different patients.

RNA analysis

Total RNA was isolated from the frozen tissues by ultracentrifugation through a cesium chloride cushion (13). Cytoplasmic RNA was extracted from the cultured cells (14). Northern blotting and hybridizations were performed as described previously (15). The relative intensities of autoradiographic signals were quantitated by densitometric scanning. All data shown here were normalized with the respective 28S ribosomal RNA values. Differences in RNA levels were assessed by the Mann-Whitney test. The level of significance was chosen as P < 0.05.

Probes

The probe for human CLA-1 mRNA was a synthetic oligonucleotide prepared at the Institute of Biotechnology, University of Helsinki (Helsinki, Finland). The sequence was 5'-CAG AAT AGG CCT GAA TGG CCT CCT TAT CCT-3', corresponding to the nucleotides 1514–1543 of the human CLA-1 mRNA (GenBank accession no. Z22555) (11). This sequence is also highly homologous to the mouse SR-BI gene, with 29 of 30 nucleotides identical to nucleotides 1495–1524 of the mouse SR-BI mRNA (GenBank accession no. U37799) (2). The mouse ribosomal 28S RNA (used as a loading control) (16) complementary DNA insert was labeled as described previously (12).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We screened 42 human adrenal samples for CLA-1 mRNA expression by Northern blots and detected abundant expression in normal adult and fetal adrenal tissues (Fig. 1Go). Northern blots hybridized with the CLA-1 oligonucleotide probe revealed a predominant transcript approximately 2.9 kilobases (kb) in size in both normal and pathological adrenal tissues. In addition, several minor transcripts of the CLA-1 gene were detected. As the relative abundance of different transcripts seemed to be fairly constant (Fig. 1Go), only the major 2.9-kb RNA species was used for statistical analysis in this study. The relative amounts of CLA-1 mRNA in all specimens studied are summarized in Table 1Go. Some variation in CLA-1 mRNA levels was evident. In general, adrenocortical hyperplasias expressed CLA-1 mRNA at higher levels than normal adrenals. The average level of CLA-1 mRNA in Cushing’s adenomas was similar to that in normal adrenals, but in the Cushing’s adenoma adjacent adrenal tissues, it was clearly lower than in these adenomas or normal adrenal tissues. Conn’s, virilizing, and clinically nonfunctional adrenocortical adenomas and their adjacent adrenal glands showed variable expression pattern of CLA-1 mRNA. On the other hand, the adrenocortical carcinomas from patients with Cushing’s syndrome, hyperaldosteronism, or virilism or without clinical evidence of steroid overproduction contained less CLA-1 mRNA than normal adrenals. Abundant expression of CLA-1 mRNA was also detected in a Leydig cell tumor, whereas liver, kidney, and pheochromocytomas expressed much less CLA-1 mRNA than the adrenocortical samples (Fig. 1Go and Table 1Go).



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  		Figure 1. CLA-1 mRNA expression in A) normal adrenals, adrenocortical hyperplasias, Conn’s and Cushing’s adenomas, and pheochromocytomas; B) an aldosterone-producing carcinoma (Conn’s carcinoma), a Cushing’s carcinoma, and a nonfunctional adrenocortical carcinoma; and C) a fetal adrenal, a virilizing adrenocortical carcinoma, a virilizing adrenal adenoma, a Leydig cell tumor (Leydigoma), and the tumor-adjacent adrenals. Total RNA was extracted from frozen tissues. The Northern blot was prepared with 20 µg RNA in each lane, and the RNA was transferred onto a nylon membrane. The filter was sequentially hybridized with a 32P-labeled CLA-1 oligonucleotide probe and a 28S ribosomal RNA complementary DNA probe. The migrations of 28S and 18S ribosomal RNAs are indicated.

 
In primary cultures of normal adrenocortical cells, CLA-1 mRNA expression was maintained at high levels for at least 2 weeks in the absence of ACTH stimulation. ACTH increased CLA-1 mRNA accumulation in a dose- and time-dependent manner. The induction by ACTH was detectable at a concentration of 30 pmol/L after 24 h of treatment. The maximal increase (3- to 7-fold over the control level; P < 0.01 in repeated experiments from four different adrenals) was reached at 3 nmol/L ACTH (Fig. 2AGo). Time-course experiments demonstrated a 50% increase in CLA-1 mRNA after 4 h of ACTH treatment, but the major induction occurred after 12 h (Fig. 2BGo). Dibutyryl cAMP [(Bu)2cAMP] also enhanced CLA-1 mRNA expression dose dependently after 24 h of treatment, with maximal stimulation at a concentration of 1 mmol/L (Fig. 3Go). ACTH and (Bu)2cAMP had no additive effect on CLA-1 mRNA accumulation (Fig. 2AGo). The protein kinase C modulator 12-O-tetradecanoyl phorbol 13-acetate (TPA; 160 nmol/L) had no significant effect on the basal CLA-1 mRNA level after 2–24 h of treatment, but it augmented ACTH-stimulated expression by about 20% (Fig. 4Go; P < 0.05; n = 3 from different adrenals). The protein kinase inhibitor staurosporine (50 nmol/L) alone increased the accumulation of CLA-1 mRNA approximately 4-fold (P < 0.01; n = 5 from different adrenals), and this stimulation was dose dependent, with detectable induction from a concentration of 5 nmol/L or greater. Staurosporine augmented the stimulatory effect of ACTH by 40%, on the average (Fig. 4Go; P < 0.05; n = 3 from different adrenals). TPA also enhanced the staurosporine-induced expression of CLA-1 mRNA by about 30% (Fig. 4Go; P < 0.05; n = 3).



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  		Figure 2. Effects of ACTH and (Bu)2cAMP on CLA-1 mRNA accumulation in primary cultures of normal adrenocortical cells. The dispersed cells were allowed to grow for 5 days before the agents were added. A, Dose-dependent effects of ACTH (picomoles per L) and interaction of ACTH (30 nmol/L) with (Bu)2cAMP (1 mmol/L) after 24 h of treatment. The Northern blot was prepared with 15 µg cytoplasmic RNA in each lane. The hybridization conditions were the same as those in Fig. 1Go. The experiment was repeated three times with cells from different patients, and the results were comparable. B, Time-dependent effect of ACTH (30 nmol/L). Each point represents the mean of three experiments (from different patients) ± range, with the control levels at each time point adjusted to 100.

 


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  		Figure 3. Dose-dependent effect of (Bu)2cAMP (micromoles per L) on CLA-1 mRNA accumulation in cultures of normal adrenal cells. The culture conditions and RNA analysis were similar to those in Fig. 2Go. The experiment was repeated twice, and the results were comparable.

 


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  		Figure 4. Regulation of CLA-1 mRNA accumulation in cultured normal adrenocortical cells by ACTH (30 nmol/L), TPA (160 nmol/L), and staurosporine (ST; 50 nmol/L). The culture method, extraction of cytoplasmic RNA, and Northern blot and hybridization conditions were the same as those in Fig. 2Go. The experiment was repeated twice with cells from different patients, and the results were similar.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cholesterol is the principal precursor for steroid biosynthesis in human steroidogenic tissues. However, little is known about the relative importance of LDL and HDL pathways for adult adrenal function. Our present data show that the putative HDL receptor, CLA-1, is abundantly expressed at the RNA level in normal and pathological adrenocortical tissues. Its predominant transcript, 2.9 kb in size, is in agreement with a previous report (11). However, we detected additional transcripts in our Northern blots, as Landschulz et al. (4) did in rat tissues. It seems that these species are alternatively spliced transcripts from the same gene, as their abundance varied in a parallel manner.

The selective cholesterol uptake pathway through the HDL receptor may be active in human adult adrenocortical cells. Patients with abetalipoproteinemia, characterized by the complete absence of all apoprotein B containing lipoproteins (chylomicrons, very low density lipoprotein, and LDL), and individuals with homozygous familial hypercholesterolemia, marked by little or no LDL receptor activity, show no evidence of adrenal insufficiency unless they are subjected to maximal stimulation with ACTH (17, 18). In the patients with homozygous familial hypercholesterolemia, using mevinolin to decrease endogenous cholesterol biosynthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase did not further impair basal or stimulated steroidogenesis (19), suggesting that cholesterol is taken up via a LDL receptor-independent pathway that could be the HDL receptor route. Our previous preliminary experiment also showed that HDL enhanced basal and ACTH-induced cortisol production in cultured adult adrenal cells (Kahri, K., HeikkiläP., et al., unpublished observation). It is also possible that the abundant expression of CLA-1 mRNA in human adrenals contributes to adrenal LDL metabolism, as it has been shown that SR-BI can bind native LDL with high affinity in vitro (1). CLA-1 mRNA is highly expressed in human fetal adrenals, which use LDL rather than HDL receptor as the major gateway of cholesterol uptake (8). Selective uptakes of LDL cholesteryl esters and HDL were parallel in rat adrenals in vivo and mouse Y1-BS1 adrenal cortical tumor cells in vitro. Both were up-regulated by ACTH, suggesting that HDL- and LDL-selective uptakes may represent the same pathway (20).

CLA-1 mRNA expression in adrenal tissues adjacent to Cushing’s adenomas was lower than that in normal adrenals. This alteration may be due to the reduced serum ACTH concentrations in these Cushing’s syndrome patients. Slightly higher CLA-1 mRNA expression in adrenocortical hyperplasias than in normal adrenals could represent ACTH-mediated induction due to the increased serum ACTH concentration present in at least some of these patients. The uptake of cholesterol and steroidogenesis in Cushing’s adenoma cells are autonomous and, thus, insensitive to the reduction of the ACTH concentration (21, 22). CLA-1 mRNA expression in adrenocortical carcinomas was slightly lower than that in normal adrenals. This is in agreement with the suggestion that ineffective or disorganized corticosteroidogenesis is characteristic of steroid metabolism in individual carcinoma cells (23).

The up-regulation of CLA-1 mRNA expression by the physiological hormone ACTH is at least in part through the cAMP-dependent protein kinase pathway, as (Bu)2cAMP treatment induced CLA-1 mRNA expression in a similar manner as ACTH, and their stimulatory effects were not additive. The coordinated induction of CLA-1 (this study) and steroidogenic enzyme gene expression (15) in adrenocortical cells further supports the assumption that CLA-1 is involved in the delivery of cholesterol into adrenocortical cells and thereby maintains adrenal cholesterol stores and corticosteroid biosynthesis. It has been shown previously that staurosporine increases steroidogenic enzyme gene expression in mouse adrenocortical Y-1 cells (24) and human fetal adrenal cells (25), suggesting that the staurosporine-sensitive protein kinase pathway has a negative tonic effect on adrenal steroidogenesis. Our present results are in agreement with these reports. The additive effect of ACTH with staurosporine and/or TPA on CLA-1 mRNA expression suggests that ACTH acts through staurosporine- and TPA-insensitive protein kinase pathways in cultured adult human adrenal cells.

In summary, our study shows that CLA-1, the human homolog to the rodent HDL receptor SR-BI, is abundantly expressed in human adrenocortical tissues at the RNA level. The accumulation of CLA-1 mRNA is up-regulated by ACTH involving the cAMP-dependent protein kinase pathway. Our data support the hypothesis that CLA-1 is a lipoprotein receptor involved in selective cholesterol uptake in human adrenocortical cells.


   Acknowledgments
 
Ms. Merja Haukka and Ms. Eija Heiliö are thanked for their technical assistance. We appreciate Ms. Johanna Joyce’s (Cambridge, UK) help in carefully reading and revising the language of the manuscript.


   Footnotes
 
1 This work was supported by the Ida Montin Foundation, the Cancer Society of Finland, and the Culture Foundation of Finland (to J.L.). Back

Received January 10, 1997.

Revised April 23, 1997.

Accepted May 1, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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