Published online before print August 25, 2005, doi: 10.1161/01.RES.0000183879.60089.a9
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Intermittent Hypoxia Induces Hyperlipidemia in Lean Mice
From the Department of Medicine, Divisions of Pulmonary and Critical Care Medicine (J.L., L.N.T., N.M.P., A.R.S., P.L.S., V.Y.P.), Endocrinology and Metabolism (R.L.M., A.R.), and Allergy and Clinical Immunology (W.C.H.), Johns Hopkins University, Baltimore, Md; and the Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine (C.-K.S., C.P.O.), University of Pittsburgh School of Medicine, Pennsylvania.
Correspondence to Vsevolod Y. Polotsky, MD, PhD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Cir, Baltimore, MD 21224. E-mail vpolots1{at}jhmi.edu
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Abstract |
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Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lepob mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl–coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.
Key Words: obstructive sleep apnea • cholesterol homeostasis • lipids • hypoxia • mouse • gene expression
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Introduction |
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Obstructive sleep apnea (SA) is the most common form of sleep-disordered breathing and is characterized by recurrent collapse of the upper airway during sleep, leading to periods of intermittent hypoxia (IH) and sleep fragmentation.1 SA is present in 2% of women and 4% of men in the general US population, but it is more common in obese individuals.2,3 SA is an independent risk factor for increased cardiovascular morbidity and mortality.4–7 It has been postulated that metabolic dysfunction in SA may provide an intermediate step linking IH and sleep disturbances to cardiovascular disease. Although several recent studies have focused on the effects of SA on dysregulating glucose and insulin metabolism,2,8–10 little information is available about the impact of SA on lipid metabolism. Abnormalities in lipid regulation that occur in response to SA may act to increase the cardiovascular risk in an already susceptible population. Although obesity is one of the risk factors for elevations in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels,11 recent clinical studies indicate that SA may also contribute to hypercholesterolemia.12–15 Thus, obesity and IH may interact to alter lipid metabolism in SA.
Key steps of lipid metabolism, including lipid biosynthesis, lipoprotein secretion, and reverse cholesterol transport, occur in the liver. Hypercholesterolemia may develop during IH as a consequence of accelerated lipid biosynthesis. Lipid biosynthesis in the liver is regulated by a family of transcription factors: sterol regulatory element binding proteins (SREBPs), which include SREBP-1a, SREBP-1c, and SREBP-2.16–18 SREBP-1a and SREBP-1c preferentially regulate enzymes of fatty acid synthesis, including acetyl coenzyme A (CoA) carboxylase,19 fatty acid synthase (FAS),20 and stearoyl-CoA desaturase 1 (SCD-1).21 SREBP-2 regulates cholesterol biosynthesis and uptake, in particular, 3-hydroxy-3-methylglutaryl (HMG)–CoA reductase and LDL receptor (LDLR).16–18,22,23 Although no previous studies have addressed whether SA can affect SREBP pathways, it is possible that IH may directly activate SREBP transcription factors in the liver to produce hyperlipidemia.
IH may also affect lipoprotein secretion and cholesterol clearance in the liver. Lipid transport into circulation is mediated mainly by apolipoprotein B (apoB).24,25 In turn, apoB traffic is facilitated by microsomal triglyceride (TG) transfer protein (MTP).26,27 Cholesterol clearance from circulation occurs via lipoprotein receptors. A key molecule of cholesterol uptake is the scavenger receptor B1 (SR-B1), which is an high-density lipoprotein (HDL) cholesterol receptor.28 The effects of IH on lipoprotein secretion and cholesterol clearance pathways are unknown.
The purpose of the current study was to examine the effects of IH on lipid metabolism in the absence and presence of obesity. We hypothesized that IH would increase serum lipid levels, and that pre-existent hyperlipidemia in obesity may modify the response. We used a previously validated mouse model of IH and examined: (1) IH-induced changes in fasting serum lipid levels in lean and genetically obese mice; (2) changes in liver lipid content in lean and obese mice exposed to IH; and (3) changes in lipid biosynthesis and lipoprotein secretion pathways and lipoprotein receptor expression in the livers of lean and obese mice exposed to IH.
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Materials and Methods |
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A total of 80 wild-type, male, lean C57BL/6J mice (lean) and 16 male obese C57BL/6J-Lepob (obese) mice from Jackson Laboratory (Bar Harbor, Maine) were used in the study. The study was approved by the Johns Hopkins University animal use and care committee and complied with the American Physiological Society Guidelines for Animal Studies. A detailed description of the experimental methods is available in the online data supplement at http://circres.ahajournals.org.
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Results |
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Serum Lipid Levels in Lean and Obese Mice Exposed to IH
Exposure to IH led to weight loss and a decrease in food intake in lean and obese mice (Table 1). In lean mice, IH resulted in increases in fasting serum TC, HDL cholesterol (HDL-C), phospholipid (PL), and TG levels compared with weight-matched control animals exposed to intermittent air (IA); whereas changes in fasting levels of LDL cholesterol (LDL-C) and free fatty acids (FFAs) did not reach statistical significance (Figure 1). In obese leptin-deficient mice, fasting serum TC, LDL-C, HDL-C, PL, TG, and FFA levels were significantly higher than in lean mice but were not affected by IH (Figure 1). IH did not increase serum total bilirubin levels, indicating that cholestasis did not play a role in the rise in serum cholesterol and PLs (Table 1). The fast protein liquid chromatography (FPLC) profile in pooled serum (Figure 2) confirmed that IH caused an increase in serum HDL-C, as determined by enzymatic assay (Figure 1), in lean mice. In IA control animals, LDL-C levels were determined by enzymatic assay and FPLC (Figures 1 and 2
). In contrast, exposure to IH led to detection of a very small LDL-C peak by FPLC, which was right shifted, consistent with the hypoxia/reoxygenation of IH oxidizing LDL-C and masking its detection by FPLC29 (Figure 2). IH also induced a 3-fold increase in serum leptin levels in lean mice, whereas fasting serum insulin and glucose levels were unchanged in both strains (Table 1).
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P<0.01 denote the difference between IH and IA within a strain.
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Liver Lipid Content in Lean and Obese Mice Exposed to IH
In lean mice, TG content of the liver was significantly elevated in response to hypoxia (18.8±3.3 mg/g of protein versus 9.6±0.7 mg/g of protein in control group; P<0.05; Figure 3A), whereas cholesterol and PL content were not affected (Figure 3B and 3C). In obese mice, TG and PL content of the liver at baseline were significantly higher than in lean mice, whereas cholesterol content at baseline was similar to the level observed in lean mice (Figure 3). IH had no effect on lipid content in the livers of the obese animals (Figure 3).
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Lipid Biosynthesis Pathways in the Liver of Lean and Obese Mice Exposed to IH
IH resulted in a significant increase of the 68-kDa active isoform of SREBP-1 in the livers of lean mice (Figure 4A). Compared with the control levels in lean mice, IH raised SREBP-1 levels by 26.7±4.0% (P<0.001; Figure 4B). In obese mice, IH did not affect SREBP-1 protein levels. Exposure to IH for 5 days led to a small but statistically significant decrease in the levels of the active isoform of SREBP-2 in the livers of lean mice (9.6±2.6% decrease; P<0.01) and obese mice (9.3±1.4% decrease; P<0.001; Figure 4C and 4D). The 125-kDa SREBP precursors were present at low levels in both strains of mice and were not affected by IH.
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Expression analysis in the liver tissue revealed that a number of enzymes of lipid biosynthesis were upregulated in obese mice compared with lean mice under hypoxic and control conditions (Table 2). These genes included FAS, acetyl-CoA synthetase, malic enzyme, and HMG-CoA reductase. The increase in active SREBP-1 in the livers of lean mice exposed to IH was associated with upregulation of the important genes of TG and PL biosynthesis such as mitochondrial glycerol-3-phosphate acyltransferase (GPAT) and SCD-1 (Table 2). A >2-fold increase in SCD-1 mRNA in lean mice exposed to IH was particularly striking, given that IH did not affect SCD-1 expression in obese mice (Table 2). Furthermore, in lean mice, IH led to a 2-fold increase in SCD-1 protein levels (Figure 5A and 5E), whereas, in obese mice, SCD-1 protein levels were unchanged. In contrast to SCD-1, IH increased mitochondrial GPAT mRNA levels not only in lean but also in obese mice (Table 2). However, protein levels of GPAT in the mitochondrial fraction of the liver (Figure 5B and 5E) and GPAT activity were not affected by IH (supplemental Figure S2, available online at http://circres.ahajournals.org). IH did not affect expression of the key genes of the SREBP-2 pathway, SREBP-2, and HMG-CoA reductase in either lean or obese mice (Table 2).
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Fatty Acid Biosynthesis and Composition
In a separate series of experiments, we examined fatty acid biosynthesis in vivo in lean mice after administration of D2O. Gas chromatography–mass spectrometry (GC-MS) detected incorporation of deuterium (D) in serum fatty acids (Figure 6A). There was no difference in serum levels of deuterated fatty acids 16:0D2, 18:0 D2, and 18:0D3 between IH and IA groups, suggesting that IH did not affect fatty acid biosynthesis de novo. In lean mice, IH changed the composition of circulating fatty acids increasing serum levels of monounsaturated species 16:1 and 18:1 (Figure 6B and 6C). In obese mice, IH did not affect serum levels of 16:1 fatty acid (Figure 6B); 18:1 levels were not determined because of technical limitations of the study.
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Lipoprotein Receptors and Pathways of Lipoprotein Secretion in the Livers of Mice Exposed to IH
In lean mice, IH augmented expression of genes controlling lipoprotein secretion, MTP, and apoB (Table 2). MTP mRNA levels in the liver were increased 2-fold, and apoB mRNA levels were increased 1.5-fold. However, IH did not have a significant effect on lipid secretion, as had been demonstrated by Triton WR-1339 administration25 (supplemental Figure S3). In obese mice, expression of MTP was significantly higher than in lean mice, and MTP and apoB were not altered by IH (Table 2).
In obese mice, baseline levels of SR-B1 mRNA were lower than in lean mice (Table 2). IH did not have a significant effect on expression of SR-B1 and LDLR mRNA in either strain of mice. IH induced a small but significant decrease in SR-B1 protein levels in the livers of lean mice (by 17.5±2.7%; P<0.001; Figure 5C and 5F) and did not affect SR-B1 protein levels in obese mice. IH increased LDLR protein levels in obese mice but not in lean mice (Figure 5D and 5F).
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Discussion |
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SA is emerging as a major cardiovascular risk factor,4–7,30 but the mechanisms of increased cardiovascular morbidity and mortality in patients with SA are still unknown. The purpose of this study was to assess the impact of IH, a key clinical manifestation of SA, on serum lipid levels and the pathways of lipid metabolism in the presence and absence of obesity. Several new findings resulted from the study. First, exposure to IH led to increases in fasting serum TC, HDL-C, PL, and TG levels in lean mice but not in leptin-deficient obese mice with hyperlipidemia at baseline. Second, exposure to IH led to increases in the liver TG content in lean mice but not in obese leptin-deficient mice. Third, in lean mice, but not in obese mice, IH increased protein levels of a key transcription factor of lipid biosynthesis in the liver: SREBP-1. Furthermore, in lean but not in obese mice, IH increased mRNA and protein levels as well as activity of SCD-1, an SREBP-1–regulated enzyme of lipid biosynthesis. Fourth, in lean but not in obese mice, IH decreased protein levels of the HDL receptor SR-B1, which is a regulator of cholesterol uptake by the liver. In this discussion, we explore the relationships and putative pathways linking lipid metabolism and IH and discuss the clinical implications of our work.
IH and Pathways of Lipid Biosynthesis
The enzymes that control lipid synthesis in the liver are coordinated by a family of SREBP transcription factors that act as master regulators.16–18,22 However, an increase in SREBP-1 levels in lean mice was not associated with increases in expression of FAS (Table 2) nor with an increase in fatty acid biosynthesis de novo (Figure 6A). Increases in GPAT mRNA (Table 2) induced by IH were not accompanied by increases in protein levels (Figure 5B and 5E) nor enzymatic activity (supplemental Figure S2) and therefore did not carry physiological significance. On the other hand, upregulation of SREBP-1 in lean mice, a phenomenon not observed in obese mice, was coupled with increases in SCD-1 mRNA and protein levels (Table 2; Figure 5A and 5E). Furthermore, IH increased the proportion of monounsaturated fatty acids (MUFAs) in murine serum in lean but not in obese mice (Figure 6B and 6C), consistent with an increase in SCD-1 activity.31,32 MUFA is a biological substrate for synthesis of TG and PL31–33; therefore, it is conceivable that increases in the liver TG and serum PL levels in lean mice exposed to IH are related to upregulation of SCD-1. Indeed, hepatic steatosis in ob/ob mice has been linked to increased SCD-1 expression and activity,34 which is confirmed by our current data (Figure 6B; Table 2). On the other hand, the SCD–/– mutation leads to low liver TG, despite normal activity of other enzymes of lipid biosynthesis.33 Thus, IH may upregulate lipid biosynthesis in the livers of lean mice via SCD-1. The pre-existing hepatosteatosis and high SCD-1 levels in ob/ob mice may offset any effects of IH.
The mechanisms of SREBP-1 and SCD-1 activation by IH are unclear. One possible mechanism of SREBP-1 activation is through insulin.35 In the current study, serum insulin levels were unchanged, a finding that does not support the role of insulin in upregulation of SREBP-1 and SCD-1 in response to IH. SREBP-1c can also be induced by elevated glucose levels, independent of insulin,36 but our data did not show significant changes in blood glucose after IH (Table 1).
Another potential mechanism of SREBP-1 and SCD-1 induction by IH would be a decrease in leptin because SREBP-1c overexpression is associated with low leptin levels.37 High levels of SCD-1 expression in leptin-deficient ob/ob mice are suppressed by leptin administration.34 However, our current and previously published findings38 indicate that IH increases serum leptin levels, which may be ascribed to the direct stimulating effects of hypoxia during the hypoxic phase39 or to the relative hyperoxia during the reoxygenation phase.40
Finally, SREBP-1 may be directly activated by hypoxia as it has been shown recently for SREBP homologs in yeast.41 Summarizing all of the above, we propose that IH enhances TG biosynthesis in the liver of lean mice via an SREBP-1–mediated increase in SCD-1 expression.
In contrast to TG biosynthesis, our data do not support a role for IH in increasing cholesterol biosynthesis. Hepatic cholesterol synthesis is predominantly regulated by the SREBP-2 transcription factor.16–18,22,23 However, hypercholesterolemia in lean mice exposed to IH was not accompanied by increases in SREBP-2 or HMG-CoA reductase levels in the liver. Therefore, it is likely that IH leads to hypercholesterolemia via mechanisms other than biosynthesis de novo.
IH and Pathways of Cholesterol Uptake and Lipoprotein Secretion
We have shown that IH led to significant increases in serum TC and HDL-C levels. The elevation in circulating HDL-C was demonstrated by enzymatic assays and FPLC (Figures 1 and 2
). IH did not affect serum LDL-C according to the enzymatic assay results (Figure 1), whereas FPLC was unable to detect a relevant peak for LDL-C in mice exposed to IH (Figure 2). The inability to detect significant LDL-C may be related to the presence of a largely oxidized form of LDL-C in mice exposed to IH,42–44 which would alter the FPLC profile for LDL-C.29 One possible explanation for the increase in HDL-C is that the clearance of cholesterol from the circulation was impaired by IH. A major pathway of cholesterol clearance from the bloodstream is the SR-B1, originally described as an HDL receptor.28 SR-B1 affinity for HDL is mediated via cholesterol esters28 and apoA-I45 in HDL particles. The SR-B1–deficient mouse has an elevation of HDL-C levels.46 In the current study, we observed that IH induced a decline in SR-B1 protein levels in the livers of lean mice without any change in LDL-R levels (Figure 5C, 5D, and 5F). Notably, SR-B1 can also mediate reuptake of PLs,47 which may contribute to an increase in circulating PLs in an analogous manner to cholesterol. Thus, a decrease in SR-B1 levels in response to IH would be consistent with our observed increase in circulating levels of HDL-C.
In ob/ob mice, IH induced an increase in LDLR protein levels without any change in SR-B1. Upregulation of LDLR did not induce any decrease in circulating cholesterol, probably because of low baseline expression of SR-B1 (Table 2).48 The low expression of SR-B1 in leptin-deficient mice results in a phenotype of elevated HDL and LDL-C,48,49 which was confirmed by our data (Figure 1). Thus, pre-existing downregulation of SR-B1 in ob/ob mice may offset any suppressive effects of IH on cholesterol reuptake by the liver.
IH also increased the expression of key genes of lipoprotein secretion: apoB and MTP (Table 2). However, IH did not affect the rate of lipid secretion into the bloodstream (supplemental Figure S3), indicating that upregulation of genes of lipoprotein secretion did not have physiological significance. Our data are consistent with the previous observations that lipoprotein secretion could be regulated at the post-transcriptional level.50 Thus, hypercholesterolemia that we observed in lean mice exposed to IH may be related to perturbations in the mechanisms of cholesterol clearance rather than lipoprotein secretion.
Clinical Implications
Our data suggest that the stimulus of IH that characterizes SA may contribute to the development of hypercholesterolemia. Consequently, the increases in cardiovascular morbidity and mortality in SA may be related, in part, to elevation in serum cholesterol levels. Unlike clinical studies, suggesting that SA is associated with decreases in HDL-C,12,13,15 we found that IH can lead to elevations in HDL cholesterol in mice, which may be related to physiological differences in cholesterol processing between species. However, IH may change properties of lipoprotein and convert HDL from anti-inflammatory antiatherogenic to proinflammatory proatherogenic factors.43,51 Hypercholesterolemia in patients with SA may be particularly detrimental because SA leads to increased lipid peroxidation.42,43,52 Oxidized LDL and PLs are taken up by macrophages more readily leading to macrophage foaming and progression of atherosclerosis.53,54
Conclusion
We have shown that IH increases fasting serum cholesterol, TG, and PL levels as well as liver TG content in lean mice, but that obesity and baseline hypercholesterolemia can mask the effects of IH on lipid metabolism. Furthermore, our data suggest that hyperlipidemia after IH may be related to changes in pathways of lipid biosynthesis and cholesterol uptake in the liver.
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute grants HL68715, HL80105, HL71506, HL37379, and HL63767. We are grateful to Dr Sandra Schreyer (AstraZeneca, Göteborg, Sweden) for donation of anti-GPAT antibodies and to Dr Joachim Herz (University of Texas Southwestern Medical Center, Dallas, Texas) for donation of anti-LDLR antibodies.
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Footnotes |
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This manuscript was sent to Stephen F. Vatner, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Original received December 9, 2004; revision received July 25, 2005; accepted August 12, 2005.
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