Published online before print March 15, 2007, doi: 10.1161/ATVBAHA.106.136382
© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
In Vivo Evidence for a Role of Adipose Tissue SR-BI in the Nutritional and Hormonal Regulation of Adiposity and Cholesterol Homeostasis
From INSERM (L.Y-C., A.B., P.B., P.F., G.D., A.Q-B.), U671, Centre Biomédical des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris6 UMR-S 671, Paris, France; INSERM (X.R.), U505, Centre Biomédical des Cordeliers, Paris, France; CNRS UMR6543 (F.M., G.A., M.T.), Centre National de la Recherche Scientifique, Nice, France.
Correspondence to Laurent Yvan-Charvet., INSERM, U671, 15 rue de l’Ecole de Médecine, 75270 Paris Cedex 06, France. E-mail ly2159{at}columbia.edu
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Abstract |
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Objectives— This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue.
Methods and Results— Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II.
Conclusions— Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.
This study shows that insulin and angiotensin II have a major role in HDL metabolism in vivo. These hormones induce redistribution of SR-BI to the plasma membrane in adipose tissue. This will then lead to an increase in LXR binding activity in an insulin and angiotensin II dependent fashion.
Key Words: adipose tissue • angiotensin II • high-density lipoprotein • insulin
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Introduction |
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Adipose tissue has a central role in the energy metabolism adaptation to the nutritional environment because of its ability to store energy as triglycerides. Besides its role in triglyceride storage, adipose tissue is also the body’s largest pool of cholesterol store, representing
25% of whole-body cholesterol in human.1 A particular interest of adipocytes is that these cells accumulate cholesterol proportionally to triglycerides. Because of an extremely low cholesterol de novo synthesis,2 adipocytes must acquire cholesterol from exogenous sources. Interestingly, clinical observations have found a correlation between obesity and low levels of high-density lipoprotein (HDL) cholesterol,3 which is the reflect of an increased incidence of atherosclerosis.4 There is also growing evidence that altered insulin sensitivity or increased angiotensin II concentrations, which occur along with obesity, play a crucial role in the acceleration of atherosclerosis but mechanisms are not yet fully deciphered.5,6 The scavenger receptor type-BI (SR-BI) has been identified as a membrane transporter involved in the selective cholesteryl esters (CEs) uptake from HDL.7 The pivotal role of SR-BI in lipoprotein metabolism and cholesterol transport in steroidogenic tissues and liver has been well-established.8 SR-BI is also expressed in adipocytes, but little is known about its function and regulation in these cells.9 Recently, studies from our laboratory have reported that SR-BI provide an important source of cholesterol from HDL in adipose cell lines and that insulin and angiotensin II induce the translocation of this receptor leading to an increase in cholesterol influx and storage.10,11 However, the nutritional and hormonal regulation of this translocation and its potential consequences on plasma HDL have not been yet explored in vivo.
Because cholesterol plays a role in the regulation of signal transduction and gene expression, we further investigated the consequence of the cholesterol influx induced by SR-BI in adipocytes. Recently, the nuclear liver X receptor (LXR), whose ligands are the oxysterols, derived from cholesterol, has been reported to regulate lipid storage in adipocytes on ligand activation.12,13 LXR activates the transcription of numerous genes involved in lipogenesis and lipid storage, especially the sterol regulatory element-binding protein-1c (SREBP-1c) transcription factor.14 SREBP-1c has been previously identified as the insulin and angiotensin II-responsive transcription factor inducing adipose lipogenesis.15,16 These findings have recently led to propose that LXR through oxysterol activation is an indirect mediator for some of insulin actions on its target gene expression.17,18
The purpose of the present study was to test in vivo the hypothesis that insulin and angiotensin II could be involved in HDL homeostasis in part through their actions in the regulation of SR-BI in adipose tissue. We then investigated the contribution of this receptor in the well-known function of insulin and angiotensin II as lipogenic hormones.
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Materials and Methods |
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For detailed descriptions of the Materials and Methods, please see supplemental material available online at http://atvb.ahajournals.org.
[3H] Cholesteryl Oleyl Ether Uptake
For the incorporation of HDL-associated [3H]CEt (4x107 cpm/mg protein), wild-type mice (Charles River Laboratories, Wilmington, Mass) were divided into 3 groups: mice were fasted for 12 hours and then intravenously injected with reconstituted HDL (2x106 cpm), followed 10 minutes later by an intraperitoneal injection of saline or insulin (Actrapid; 0.01 U/ mouse). In another group, mice were refed for 12 hours and injected with the reconstituted HDL. One hour after tracer injection, mice were euthanized, and blood was collected by cardiac punctation. Epididymal fat pads and liver were harvested, and tissue content of [3H]CEt radioactivity was measured after lipid extraction. The total uptake attributed to each organ was expressed as the radioactivity recovered in that organ over the total radioactivity injected. Assuming that epididymal adipose tissue contributes to one-fifth of total adipose tissue,19 and reflects the metabolic behavior of all adipose tissue, the total [3H] cholesteryl oleyl ether uptake attributed to total fat was calculated and expressed as percent of injected dose.
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Results |
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HDL Cholesterol Uptake by Adipose Tissue
We first determined in vivo the ability of adipose tissue to bind apolipoproteins and, thus, to capture cholesterol from HDL. Supplemental Figure IA (please see http://atvb.ahajournals.org) depicts apolipoproteins distribution in adipose cells membranes (supplemental Figure IA) and cholesteryl-Bodipy into the cells (supplemental Figure IB) 1 hour after intravenous injection of labeled HDL in fed male mice, with no colocalization between these 2 fluorescent dyes (supplemental Figure ID). These results confirm in vivo that uptake and routing of sterols from HDL in adipose tissue were functional.
Insulin and Angiotensin II Induce the Translocation of SR-BI in Adipose Tissue and Decrease Plasma HDL
To evaluate whether insulin and angiotensin II could affect HDL cholesterol uptake in adipose tissue, these hormones were intraperitoneally injected in 2-hour fasted wild-type mice and SR-BI expression was determined. One hour after injection, the short insulin or angiotensin II exposure had no effect on SR-BI mRNA expression (data not shown). However, immunoblot of subcellular membrane fractions revealed that insulin rapidly induced the SR-BI abundance in the plasma membrane (2-fold increase) to the detriment of SR-BI in the high-density microsome fraction (2-fold decrease; Figure 1A). Little SR-BI immunoreactivity was observed in the low-density microsomes fraction (Figure 1A). Angiotensin II intraperitoneal injection revealed similar findings because SR-BI was increased by >50% in the adipose tissue plasma membrane fraction and decreased by 60% in the high-density microsome fraction (Figure 1B). These results prompted us to evaluate the consequence of insulin and angiotensin II intraperitoneal injection on plasma HDL. Both insulin and angiotensin II rapidly decreased plasma HDL cholesterol since the first hour, leading to 30% decrease after 120 minutes as compared with saline injection (Figure 1C). Therefore, acute action of insulin and angiotensin II stimulate in vivo intracellular SR-BI translocation to the adipocytes plasma membrane and decrease plasma HDL.
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Refeeding and adipose angiotensinogen overexpression induce an increase in both adipose SR-BI translocation and SR-BI mRNA expression. We therefore investigated SR-BI translocation and plasma HDL in states involving either high insulin concentration, such as refeeding, or high angiotensin II concentration, such as in transgenic mice overexpressing angiotensinogen in adipose tissue (Ovex mice). The phenotypic characteristics of the mice used in this study are shown in Table 1. Immunoblots of adipose tissue revealed that SR-BI was increased by 2-fold in the plasma membrane fraction not only in wild-type mice after refeeding but also in Ovex mice as compared with controls (Figure 2A and 2B). These results show that the changes in insulin- or angiotensin II-induced SR-BI translocation could also be functional in refeeding state or in angiotensinogen transgenic mice. However, the observed increase of SR-BI in the adipose high-density microsome fraction of refed and Ovex mice indicated that the total amount of SR-BI was increased in these models (Figure 2A and 2B). This was consistent with the higher SR-BI mRNA levels observed in adipose tissue from refed mice as compared with fasted mice (4-fold; Figure 2C) and from Ovex mice as compared with WT mice (2-fold; Figure 2D). We next observed that plasma HDL was decreased by >40% after refeeding, along with a significant increase in adipose tissue cholesterol content (1.8-fold; Table 1). Similar findings were observed in Ovex mice, which overexpress angiotensinogen specifically in adipose tissue, because plasma HDL was significantly decreased by 20% as compared with wild-type mice along with a 30% increase in adipose tissue cholesterol content (Table 1). Taken together, these results suggest that insulin and angiotensin II regulate SR-BI through transcriptional and posttranscriptional mechanisms. Such a regulation could largely contribute to the increased cholesterol content in adipose tissue along with the decrease in plasma HDL.
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Accumulation of HDL [3H] Cholesteryl Oleyl Ether in Epididymal Adipose Tissue
To confirm that HDL cholesterol uptake in adipose tissue was sensitive to nutritional and hormonal regulation, HDL labeled with [3H]CEt was injected in fasted mice, fasted mice injected with insulin, or 12-hour refed mice. After 1 hour, insulin tented to significantly decrease the plasma radioactivity by 25%, and refeeding decreased the plasma radioactivity by 35% (Table 2). In fasted mice, based on the fact that 0.5% of the injected dose of HDL-associated [3H]CEt appeared in epididymal fat pads, we estimated that total fat mass incorporated 2.5% (see Materials and Methods and Table 2). This amount was increased 3-fold in fasted mice injected with insulin and 7.5-fold in 12-hour refed mice (Table 2). As expected, the liver accounted for a large amount of radiolabeled HDL cholesterol uptake as compared with adipose tissue (15%; Table 2). However, this amount was slightly but not significantly increased after insulin injection (1.2-fold) and increased after refeeding to a lesser extent than adipose tissue (1.5-fold). These results confirm that adipose tissue plays a crucial role in HDL cholesterol homeostasis.
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HDL Induces Triglyceride Storage by a LXR-Dependent Pathway Through SR-BI
The increased adipose tissue cholesterol content in refed mice or in Ovex mice along with the triglycerides content (Table 1) raised the question of the potential role of SR-BI in the control of triglyceride metabolism. Figure 3A also reveals that during the differentiation of 3T3-L1 cell line with formation of large intracellular triglyceride droplets, a strong induction of SR-BI mRNA expression occurred and positive correlations were observed with cholesterol accumulation (R2=0.93). Interestingly, addition of HDL (20 µg protein/mL) in lipoprotein-deficient serum medium increased cell triglyceride content by 20% within 5 hours and by almost 40% after 24 hours. This accumulation was completely inhibited by the presence of a blocking SR-BI antibody (Figure 3B). Moreover, 5-hour HDL treatment significantly increased the mRNA content of genes involved in lipogenesis pathway in a SR-BI–dependent fashion (Figure 3C). We reported that expression of ABCA1 was also increased by HDL and prevented by the blocking SR-BI antibody (Figure 3C). These genes are well-known targets of the nuclear LXR. We then assessed the potential LXR binding activity in 3T3-L1 adipocytes cultured in presence of HDL by EMSA using the LXRE-binding site of the SREBP-1c promoter. In cells cultured in lipoprotein-deficient serum medium, no LXR binding activity was detected (Figure 3D). By contrast, a strong induction of LXR binding activity was observed when the cells were cultured in presence of HDL in the medium. This was prevented by the presence of blocking SR-BI antibody (Figure 3D). The specificity of the LXR binding activity was confirmed by unlabeled DNA competition of the HDL-stimulated condition. Therefore, HDL triggers lipid storage through an LXR nuclear activation.
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Insulin and Angiotensin II Stimulate HDL-Induced LXR Target Genes
We next investigated the roles of insulin and angiotensin II in the induction of LXR target genes in the presence of HDL. We reported that neither insulin nor angiotensin II alone was able to stimulate ABCA1 expression in fully differentiated 3T3-L1 cells (Figure 4A). Nevertheless, in presence of HDL, both insulin and angiotensin II significantly increased the amount of ABCA1 mRNA by 60% as compared with HDL-treated cells (Figure 4A). These inductions were prevented by the presence of blocking SR-BI antibody (Figure 4A). In contrast to what is observed with ABCA1, SREBP-1c mRNA was significantly increased by insulin alone (40%) and tended to be increase by angiotensin II alone after a 5-hour treatment (Figure 4B). In addition, insulin and angiotensin II stimulated HDL-induced SREBP-1c mRNA levels by 1.8-fold and 2-fold, respectively, as compared with HDL-treated cells, and a blocking SR-BI antibody abolished this additional effect (Figure 4B). Thus, we propose SR-BI as a new candidate for insulin- and angiotensin II-enhanced lipogenesis in adipocytes.
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Discussion |
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Adipocytes abundantly express SR-BI, and it is likely that these cells capture significant amounts of CEs through the classical HDL delivery mechanism in vitro.10,20 Our data reveal that the selective uptake of CE from HDL in adipose tissue is functional in vivo and can be regulated by both insulin and angiotensin II. Indeed, these hormones rapidly increase in vivo the translocation of SR-BI to the adipose tissue plasma membrane. This is in agreement with a recent report from our laboratory showing that insulin and angiotensin II induce SR-BI translocation in vitro, leading to an increased cholesterol influx from HDL.11 Because adipose tissue is not only one of the main insulin-sensitive organs but also the body’s largest pool for cholesterol, this raises an intriguing question: how could insulin and angiotensin II contribute to the plasma HDL homeostasis? Interestingly, we report here that both insulin and angiotensin II are able to rapidly decrease plasma HDL cholesterol.
A previous study by Glass et al21 revealed that epididymal fat pads accounted for a small part in the uptake of HDL-associated CE in fasted rats. However, little attention has been placed on the metabolism of HDL cholesterol in different conditions such as increased insulinemia in refed animals or enlargement of adipose tissue in obesity. The bulk of our results reveals that adipose tissue CE uptake is sensitive to the nutritional status and could participate in plasma HDL clearance in vivo. Obviously, the liver is a major organ for HDL-selective CE uptake21 and it could be involved in the insulin- and angiotensin II-induced HDL clearance. Recently, Shetty and al22 revealed that insulin increased cell surface expression of SR-BI in HepG2 cells. However, insulin intraperitoneal injection in wild-type mice did not significantly increase hepatic selective CE uptake or SR-BI content in liver plasma membrane (data not shown). Such discrepancy between in vitro and in vivo system remains to be elucidated. Nevertheless, our study cannot completely exclude a role for the liver in the hormonal and nutritional regulation of HDL cholesterol homeostasis because a slight variation in the large amount of hepatic HDL selective CE uptake could largely contribute to circulating HDL cholesterol. Thus, besides their role in inflammation and mechanical stress-induced atherosclerosis,23,24 insulin and angiotensin II are also involved in plasma HDL homeostasis.
Refeeding and transgenic mice overexpressing angiotensinogen specifically in adipose tissue (Ovex mice) are conditions leading to an increase in plasma insulin or angiotensin II. After refeeding, the decreased plasma HDL along with the increased adipose tissue cholesterol content are consistent with previous studies reporting that adipose tissue cholesterol levels are dependent on nutritional conditions and that plasma cholesterol could be in equilibrium with adiposity.2,25 Interestingly, hepatic HDL-selective CE uptake was also sensitive to refeeding, but the mechanism remains to be clarified. We also report for the first time that overexpression of angiotensinogen locally in adipose tissue leads to a similar phenotype. In these conditions, SR-BI proteins are not only regulated through posttranscriptional mechanisms but also at transcriptional levels. Interestingly, insulin and angiotensin II have been previously reported to increase SR-BI mRNA expression in 3T3-L1 adipocytes or in other cells type.26,27 We thus propose a mechanism in which increased insulinemia that occurs during refeeding or increased angiotensin II in Ovex mice could account for the induction of SR-BI expression and adipose tissue plasma membrane translocation. This regulation could contribute to the increased adipose tissue cholesterol storage in conjunction with the insulin- and angiotensin II- related stimulation of lipogenesis.
Cholesterol homeostasis plays a crucial role in the regulation of signal transduction in adipocytes and could be involved in the process of triglyceride storage.28 Adipose cholesterol content is increased in refed mice or in Ovex mice along with triglyceride. In addition, a strong induction of cholesterol storage along with SR-BI expression occurred during the course of adipocyte differentiation and triglyceride storage. Previous works, in which 3T3-L1 cells were treated during the course of differentiation, revealed that HDL increased triglyceride storage.29 The present study demonstrates that treatment of fully differentiated 3T3-L1 adipocytes with HDL also induce triglyceride storage, and this occurs in SR-BI–dependent fashion. Further information should be provided by the generation of transgenic mice overexpressing SR-BI in adipose tissue. Thus, these results suggest that cholesterol from HDL could be a signal that triggers lipid storage.
The LXR is a nuclear receptor for which endogenous ligands are oxysterols (intermediates of cholesterol metabolism).30 This nuclear receptor is involved in adipocyte lipid metabolism by inducing several lipid-related genes and lipogenesis.12,13 Our study reveals that SR-BI, which mediates the selective uptake of cholesterol from HDL, seems to be a determinant step in the induction of LXR binding activity in adipose tissue. As expected, insulin and angiotensin II on their own are able to stimulate SREBP-1c expression in 3T3-L1 adipocytes.15,16 However, we reported that both insulin and angiotensin II are able to stimulate the action of HDL on LXR target genes, SREBP-1c and ABCA1, in SR-BI–dependent fashion. This suggests a new mechanism action for the lipogenic hormones that could have major interest in vivo in a context where adipose tissue is exposed to circulating lipoproteins such as HDL. The fact that refeeding and angiotensinogen overexpression increase adipose tissue cholesterol content in vivo is in line with our results and point out new insight into how insulin and angiotensin could govern lipid metabolism in vivo in adipose tissue.
In conclusion, our observations provide the first in vivo evidence that insulin and angiotensin II can participate in HDL homeostasis through action on the translocation of SR-BI in adipose tissue. Such a role of insulin and angiotensin II might be physiologically important in the control of adiposity and raise a potential new link between obesity, insulin-resistance, and atherosclerosis.
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Acknowledgments |
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The authors thank Dr Huby for scientific discussion.
Sources of Funding
This work was supported by grants from The Fondation de France and INSERM.
Disclosures
None.
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Footnotes |
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Original received August 18, 2006; final version accepted March 4, 2007.
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