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Original Studies |
Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System (S.A., L.T., S.M., E.R.), Palo Alto, California 94304; and the Department of Gynecology and Obstetrics, Stanford University Medical Center (Y.C., L.G.), Stanford, California 94305
Address all correspondence and requests for reprints to: S. Azhar, Ph.D., Geriatric Research, Education, and Clinical Center, 182B, Veterans Administration Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In rodents, the selective pathway appears capable of using lipoproteins with diverse apoprotein patterns. For example, the predominant circulating lipoprotein in the rat is high density lipoprotein (HDL)-containing apolipoprotein A1 (apo A1) and apo E, and this lipopoprotein has high affinity for rat granulosa cells used as a model cell culture system in our laboratory (10, 14, 16). However, the selective pathway in these cells also recognizes apo E-free human HDL (hHDL3) containing only apo A1 and A11, rat LDL containing apo B and apo E, and human LDL containing only apo B (10, 14). Recent studies from two different laboratories suggest that the previously cloned type I, class B scavenger receptor (SR-BI) may be the lipoprotein receptor that mediates the uptake of CE through the selective pathway (29, 30, 31, 32).
Although various lipoproteins are capable of delivering their CEs to cells via the selective pathway, the efficiency by which this occurs in rat tissues varies with the cell type, the metabolic state of the cell, and the lipoprotein particle provided (2, 4, 6, 7, 8, 9, 14, 33, 34, 35, 36). Thus, intact tissues and isolated cell preparations from the same steroidogenic organs in culture often show different preferences in the pathway used and in the efficiency by which CEs are obtained from different lipoproteins (7, 10, 14, 33, 34, 35, 36). Indeed, some cultured cells that are not prestimulated to produce steroid hormones [such as rat granulosa cells before trophic hormone or dibutyryl cAMP (Bt2cAMP) treatment] do not selectively internalize and transport lipoprotein CEs at all (16).
These issues regarding use of the selective pathway and diverse lipoproteins have led to the current study in which granulosa cells were obtained from humans, a species in which LDL, not HDL, is the primary circulating lipoprotein and in which the LDL (B/E) receptor pathway for cholesterol uptake is highly developed (37, 38, 39, 40, 41). The primary question in this report has to do with whether human granulosa cells selectively internalize lipoprotein CEs for steroidogenesis. If so, do human cells preferentially use HDL or LDL in this pathway and are the characteristics of this pathway similar to those described previously in rat granulosa cells. These issues concerning HDL are of interest because a considerable literature exists that claims that human granulosa cells either do not use HDL for progesterone production (42) or use HDL less efficiently than LDL for steroidogenesis (39), or that the addition of hHDL3 to human granulosa cells actually inhibits progesterone production (37, 40). Based on these reports, one would not anticipate the selective uptake of HDL cholesterol in human cells. On the other hand, several investigators (43, 44) have reported that the follicular fluid of most preovulatory follicles obtained from patients undergoing in vitro fertilization-embryo transfer (IVF-ET) procedures contain only HDL lipoproteins; i.e. the presence of LDL in the follicular fluid appears in less than 10% of retrieved follicles. Thus, the role of HDL in follicle physiology is not entirely clear, and it may be that this lipoprotein is, in fact, a normal supplier of cholesterol to granulosa cells stimulated to produce high levels of progesterone.
The current study was designed to address the issue of whether human granulosa cells selectively internalize and use HDL-donated CEs. Human granulosa/luteal cells were obtained from patients undergoing controlled ovarian hyperstimulation and IVF-ET. Measurements of lipoprotein-induced progesterone production were correlated with lipoprotein-derived CE uptake by either the selective or endocytic pathways, as viewed by both biochemical and morphological techniques. Insofar as the selective pathway was found to be active in human granulosa cells, its regulatory characteristics were subsequently compared with those identified previously in rat cells.
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Materials and Methods |
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[1
,2-N-3H]Cholesteryl oleolyl ether [1.85
tetrabecquerels (TBq)/mmol; 50 Ci/mmol] was purchased from Amersham
Corp. (Arlington Heights, IL). [9,10-N-3H]Oleic acid
(2.22 TBq/mmol; 60 Ci/mmol) and [1-14C]cholesteryl (1.85
GBq/mmol; 50 mCi/mmol) were obtained from American Radiolabeled
Chemicals (St. Louis, MO). [1,2-N-3H]progesterone (2.1
TBq/mmol; 57 Ci/mmol),
[1,2-N-3H]20-hydroxypregn-4-ene-3-one (1.9 TBq/mmol;
51.2 Ci/mmol), and Na125I (carrier-free; 643.8 GBq/mg; 17.4
Ci/mg) were supplied by DuPont-New England Nuclear Research Products
(Boston, MA). The following chemicals were the products of Sigma
Chemical Co. (St. Louis, MO): Bt2cAMP, cholesteryl oleate,
triolein, hydrocortisone, progesterone, 20-hydroxypregn-4-ene-3-one,
and 17ß-estradiol. Human plasma transferrin, human plasma
fibronectin, and insulin were obtained from Collaborative Research
(Bedford, MA). Cholesteryl
4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-S-indacene-3-dodecanoate
(cholesteryl BODIPY FL C12) was purchased from Molecular Probes
(Eugene, OR). All other reagents used were of analytical grade.
Cell collection
Granulosa cells were collected by aspiration of follicles from women who underwent ultrasound-guided transvaginal oocyte retrieval for IVF-ET (45) after giving written informal consent. Pituitary desensitization was achieved with leuprolide acetate (Lupron, TAP Pharmaceuticals, North Chicago, IL; 1 mg, sc, daily beginning 1 week before the anticipated menses). On day 3 of the next cycle, if serum estradiol was less than 40 pg/mL, leuprolide acetate was decreased to 0.5 mg, sc, daily, and im administration of human menopausal gonadotropin (Pergonal, Serono, Randolph, MA) was begun. When follicular development appeared adequate by vaginal ultrasound and serum estradiol levels, 5000 IU hCG (Profasi, Serono Laboratories, Braintree, MA) were administered, and follicles were aspirated transvaginally 34 h later. Only follicular fluid not contaminated with blood was used.
Luteinizing granulosa cells in the aspirated fluid were collected by centrifugation at 300 x g for 5 min, followed by resuspension in saline. Granulosa cells were purified by Percoll density gradient centrifugation and plated on fibronectin-coated dishes (45). For the first 18–24 h, the cells were cultured with complete DMEM-Ham’s F-12 medium containing 5% FCS, 2 µg/mL bovine insulin, 5 µg/mL human transferrin, and 100 ng/mL hydrocortisone; thereafter, the cells were maintained without added serum (10, 14, 45).
Lipoprotein preparation
hLDL and apo E free hHDL3 were isolated as previously described (10, 14, 16). For uptake and internalization studies, lipoproteins were conjugated with residualizing labels, i.e. 125I-labeled dilactitol tyramine (DLT) and [3H]cholesteryl oleolyl ether (COE) (7, 10, 16). For fluorescence microscopy studies, reconstituted (rec-) cholesteryl BODIPY HDL particles were prepared as described previously (10, 16).
Steroidogenic response
To assay steroidogenesis, triplicate dishes of cultured
granulosa cells were supplemented with Bt2cAMP (2.5 mmol/L)
and hHDL3 (500 µg protein/mL) or hLDL (100 µg
protein/mL) and incubated for 3, 6, 9, and 24 h; samples of
incubation medium were frozen and stored until assayed for progestins.
Progesterone and its metabolite (20-hydroxypregn-4ene-3-one) were
quantified by RIA using specific antiserum as described previously
(10). Unless otherwise stated, results are expressed as nanograms of
progesterone produced per µg DNA and represent the mean ±
SE of duplicate determinations of three different
dishes.
CE uptake
Granulosa cells cultured for 48 h were incubated with [125I]DLT-[3H]COE hLDL (50 µg/mL) or hHDL3 (100 µg/mL) for 3, 6, and 24 h at 37 C. At the end of incubation, the cells were processed for determining 125I radioactivity or were extracted with organic solvents to determine 3H radioactivity (7, 10, 14). From these data, the relative amounts of CEs and apoproteins internalized via the endocytic and selective pathways were computed (7, 10, 14, 35); results are expressed as the net mass of CEs internalized. The sum of selective plus endocytic uptake is shown as the total uptake of CEs.
Confocal microscopic CE-BODIPY fluorescence
To evaluate the uptake and direct accumulation of HDL-provided CE, granulosa cells were grown on fibronectin-coated UV-treated glass coverslips for 72 h, then treated with (or without) Bt2cAMP for 24 h before incubation with rec-HDL (BODIPY-CE-HDL) for varying time periods. After incubation, coverslips were washed three or four times with PBS, fixed with 1.5% glutaraldehyde in PBS for 5 min, washed again, and mounted with PBS on slides immediately before viewing. Imaging was carried out with a custom-built, mirror-scanning, single beam laser confocal microscope (designed by S. Smith, Stanford University, Stanford, CA). The samples were excited at 488 nm, and observations were made at 510–550 nm with a Nikon 60X (NA 1.4) planapo objective (Nikon Corp., Melville, NY). The fluorescent images were stored in a computer and subsequently processed in grayscale or color using Adobe Photoshop.
Fluorometric measurement of total CE-BODIPY fluorescence
Cells were incubated with rec-HDL (BODIPY-CE-HDL; 50 µg/mL) for 60–180 min. After incubation, the cell preparations were washed, and total lipids were extracted with hexane-isopropyl alcohol (3:2, vol/vol) as described previously (14). In each case, the fluorescence of a suitably diluted aliquot of hexane-isopropyl alcohol extract was measured at an excitation wavelength of 503 nm and an emission wavelength of 512 nm using a Perkin-Elmer 650–40 fluorescence spectrometer (Perkin-Elmer, Palo Alto, CA). The results are expressed as arbitrary units per µg DNA and represent total CE-BODIPY uptake by granulosa cells.
Esterification of [3H]oleic acid into cellular CE
Granulosa cells were exposed to a [3H]sodium oleate-albumin mixture (final concentration, 100 µmol/L oleate-20 µmol/L albumin) with hHDL3 (500 µg protein/mL), hLDL (100 µg protein/mL), Bt2cAMP (2.5 mmol/L), or aminoglutethimide (AMG; 100 µmol/L), a specific inhibitor of cholesterol side-chain cleavage cytochrome P450 (39), for 24 h at 37 C. Cell lipids were extracted in hexane-isopropyl alcohol (3:2). Radioactivity in cellular CEs was assessed after separation from other cellular lipids by thin layer chromatography (14).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Steroidogenic response of human granulosa cells to lipoproteins
Human granulosa cells obtained from the trophic hormone-primed
women of this study primarily secrete the steroid hormone, progesterone
(Fig. 1
). In the basal state, the cells
secrete only minor quantities of the hormone; this small response
occurs despite the fact that microscopically the cells appear to be
well stocked with intracellular lipid. With the addition of
lipoproteins (either hHDL3 or hLDL), the level of
progesterone production and secretion is increased several fold (Fig. 1). The further addition of Bt2cAMP more than doubles the
effect of using lipoproteins alone, and this heightened response occurs
equally with hHDL3 and hLDL (Fig. 1).
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shows the 24-h response of
granulosa cells from a single subject. Without Bt2cAMP
treatment, relatively minor amounts of progesterone are made during the
24-h interval, although the addition of lipoproteins stimulates this
response. Coincubation of granulosa cells with lipoproteins and
Bt2cAMP greatly enhances the response; this response is
seen in 3 h and shows a linear increase between 6 and 24 h,
with hHDL3 and hLDL having an identical stimulatory
effect.
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Given the clear-cut secretory response of human granulosa cells
when incubated with either HDL3 or LDL, it was of interest
to determine which of the cholesterol uptake pathways was used for the
processing of these lipoproteins. Table 1
presents separate CE uptake data from isolated granulosa cells of four
different individuals. There is variation among the patients, but
similar trends are seen. Overall, the data indicate that total CE
uptake from HDL is 2–3 times that of CE uptake from LDL. With
HDL3, 95% of this total derived CE is internalized via the
selective pathway. With LDL, most (60–70%) CE is taken up through the
endocytic pathway. Figure 3 describes the
24-h selective pathway uptake of lipoprotein CE with granulosa cells
taken from one patient. As previously noted (10, 14), LDL-CE-selective
uptake (with or without cAMP) is minor compared to HDL-CE-selective
uptake, which shows a linear increase starting with the initial point
of measurement (3 h) and continuing through 24 h. With luteinized
granulosa cells such as used in these experiments, coincubation with
Bt2cAMP does not greatly affect the uptake of CEs.
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The aim of these experiments was to determine whether
internalized, native hHDL3-CE, (like LDL-CE) is processed
efficiently by human granulosa cells, i.e. available for
hydrolysis and reesterification and/or normally used in granulosa cell
progesterone secretion. Granulosa cells were incubated with native
hHDL3 (or hLDL as a control), and oleate formation was
tracked with the use of radiolabeled oleic acid under different
conditions. AMG was added to block steroidogenesis (see Fig. 4) and, in so doing, to identify free
cholesterol (otherwise used for steroidogenesis) now available for
reesterification (with radiolabeled oleic acid), storage, and
measurement.
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indicates that hydrolysis, reesterification, and/or
utilization of hHDL3-CE in human granulosa cells is totally
dependent on cell stimulation. In unstimulated cells (not provided with
Bt2cAMP in vitro), HDL3 supplies no
more than basal levels of free cholesterol for esterification or
steroidogenesis. In Bt2cAMP-treated cells, the provision of
hHDL3 alone does not appear to increase esterification, but
the use of the hHDL3 plus AMG block produces a 5-fold
increase in cholesterol availability for esterification. These findings
suggests that in cAMP-stimulated human granulosa cells, hHDL-CE is
normally hydrolyzed to free cholesterol, which is immediately used in
steroidogenesis (and, therefore, is not available for esterification),
but once the steroidogenic pathway is blocked, this free cholesterol
becomes available for reesterification and storage. In contrast,
hLDL-CE use is less specialized, and free cholesterol is available for
reesterification by the human granulosa cells regardless of whether the
cells are further stimulated with cAMP or blocked with AMG. Characteristics of selective uptake of HDL-CEs
For these experiments, human granulosa cells were incubated with reconstituted apo E free hHDL prepared with BODIPY-CE, [fluorescently labeled lauric acid associated with cholesterol through an ester linkage (14, 16)] and viewed by confocal microscopy. BODIPY-CE is a good substrate for acidic (lysosomal) CE present as part of the endocytic (LDL, B/E receptor) pathway (16), but when hydrolyzed, the BODIPY label dissipates and is lost to follow-up (16). On the other hand, BODIPY-CE is not hydrolyzed by neutral (cytosolic) CE, and CEs entering cells by a nonlysosomal pathway remain intact. Thus, all visible fluorescence remaining in the cells at the end of experiments is known to represent newly internalized HDL-derived CE internalized exclusively through the selective pathway.
Effect of cAMP. Human granulosa cells incubated for 3 h
with reconstituted BODIPY-CE HDL internalize and store large quantities
of BODIPY-CE, as demonstrated by the fluorescent (white) cytoplasmic
droplets seen in the cells in Fig. 5. The
internalized BODIPY-CE appears as an accumulation of fluorescent
droplets corresponding to lipid storage droplets visible by phase
microscopy in the same cells (14, 16). No appreciable differences are
seen in the uptake of the BODIPY marker if the cells are incubated in
the presence or absence of Bt2cAMP (Fig. 5, A
vs. B).
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indicates that human granulosa cells
incubated with BODIPY-CE HDL (without Bt2cAMP) show no
BODIPY label at zero time, but have a rapid onset and steadily
increasing uptake of the BODIPY label throughout the 6-h experimental
interval; low levels of fluorescence are shown as a greenish yellow
color, medium levels of fluorescence as yellow, and high levels of
fluorescence as red. After 5 min of incubation with the BODIPY label
(Fig. 6B), the cytoplasm of the granulosa cells shows a faint,
reticular labeling of a greenish yellow hue, with an occasional yellow
or reddish granule in the field. After 15 min (Fig. 6C), the reticular
background labeling is enhanced, and more yellow and red droplets of
BODIPY are present. By 1 h (Fig. 6D), all cells are filled with
yellow and red droplets, and by 3 h (Fig. 6E) and 6 h (Fig. 6F), the cells are so filled with the BODIPY-CE that the lipid appears
to have fused into large pools.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One wonders how such a clear-cut result with HDL can be reconciled with observations from several earlier reports stating that HDL is not an effective cholesterol donor for human granulosa cell steroidogenesis (37, 38, 39, 40, 41, 42). Perhaps these conflicting results reflect nothing more than the use of differing culture conditions; i.e. cells exposed to lipoproteins before incubation with HDL during the steroidogenic interval do not show an increase in steroid production (37, 38, 39, 40, 41, 42), whereas cells not previously exposed to lipoproteins (such as in the current study) do respond (46, 47).
The finding that human granulosa cells use HDL cholesterol for steroidogenesis brings up the question of which cholesterol uptake pathway is used. Quantitative results from the current experiments using radiolabeled nonreleasable apolipoprotein and cholesteryl ester tags indicate that more than 95% of the mass of HDL-CE enters human granulosa cells through the nonlysosomal, selective pathway; i.e. CEs are released from HDL and are taken up directly by the cells, without internalization of the lipoprotein itself. This CE can be directly used in steroidogenesis (see reesterification studies with AMG) or stored. Also, confocal microscopic studies with the BODIPY-CE HDL provide evidence that human cells, like rodent cells (14, 16), can selectively internalize and store CE without prior hydrolysis of the CE molecule.
In addition, the BODIPY-HDL studies indicate that the selective uptake of CE is both rapid and efficient. Cytoplasmic BODIPY-CE uptake is visible as early as 5 min after incubation of the cells with the reconstituted HDL, and labeled cytoplasmic lipid droplets are plentiful by 15 min. By 3 h, when the increase in steroidogenesis is barely recognized biochemically, confocal microscopic studies show that the granulosa cell cytoplasm is already filled with newly acquired (fluorescent) CE. Indeed, biochemical procedures to quantify granulosa cell internalization of HDL-CE indicate a steady linear increase in CE uptake over the 24-h interval examined. In regard to this storage function, HDL represents the preferred ligand and delivers 2–3 times more CE than does LDL under the same conditions. Remarkably, this occurs regardless of whether the cells are coincubated with B2cAMP, and one suspects that cell luteinization as a result of prehormone treatment of the donor patients is a powerful factor.
This selective HDL-CE uptake and intracellular traffic in human granulosa cells appears to be regulated by some of the same factors operating in rodent cells (14, 16). Uptake and storage in human cells is temperature dependent and energy sensitive, is blocked by sulfhydryl-active agents such as NEM, and is independent of small, soluble steroid carrier proteins, such as those likely to leak from cells after permeabilization procedures.
Thus, when considering the acquisition of CE as a substrate for steroid hormone production, the human cells of this study are, in every measurable way, similar to granulosa cells obtained from rodents. Despite the fact that the blood lipid profiles of humans are so different from those of rodents (48), despite the presence of the LDL uptake pathway in human steroidogenic cells (37, 38, 39, 40, 41), and despite previous reports claiming that luteinized granulosa cells do not use HDL for hormone production (37, 38, 39, 40, 41, 42), our findings indicate that luteinized granulosa cells from hormone-primed healthy young women efficiently take up, metabolize, and use HDL-derived cholesterol for steroidogenesis.
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Footnotes |
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Received August 20, 1997.
Revised November 7, 1997.
Accepted December 3, 1997.
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