Published online before print September 15, 2008, doi: 10.1161/CIRCULATIONAHA.108.793182
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(Circulation. 2008;118:1467-1475.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Inhibition of Stearoyl-Coenzyme A Desaturase 1 Dissociates Insulin Resistance and Obesity From Atherosclerosis
From the Department of Pathology, Section on Lipid Sciences (J.M.B., S.C., J.K.S., C.D., T.N., X.Z., M.-N.D., R.S., M.A.D., K.K., M.D.W., C.K., J.S.P., L.L.R.), Department of Biochemistry (H.M.A.), and Department of Molecular Medicine (A.L.W.), Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Lawrence L. Rudel, Wake Forest University School of Medicine, Department of Pathology, Section on Lipid Sciences, Medical Center Blvd, Winston-Salem, NC 27157–1040. E-mail lrudel{at}wfubmc.edu
Received May 19, 2008; accepted August 4, 2008.
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Abstract |
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Background— Stearoyl-coenzyme A desaturase 1 (SCD1) is a well-known enhancer of the metabolic syndrome. The purpose of the present study was to investigate the role of SCD1 in lipoprotein metabolism and atherosclerosis progression.
Methods and Results— Antisense oligonucleotides were used to inhibit SCD1 in a mouse model of hyperlipidemia and atherosclerosis (LDLr–/–Apob100/100). In agreement with previous reports, inhibition of SCD1 protected against diet-induced obesity, insulin resistance, and hepatic steatosis. Unexpectedly, however, SCD1 inhibition strongly promoted aortic atherosclerosis, which could not be reversed by dietary oleate. Further analyses revealed that SCD1 inhibition promoted accumulation of saturated fatty acids in plasma and tissues and reduced plasma triglyceride, yet had little impact on low-density lipoprotein cholesterol. Because dietary saturated fatty acids have been shown to promote inflammation through toll-like receptor 4, we examined macrophage toll-like receptor 4 function. Interestingly, SCD1 inhibition resulted in alterations in macrophage membrane lipid composition and marked hypersensitivity to toll-like receptor 4 agonists.
Conclusions— This study demonstrates that atherosclerosis can occur independently of obesity and insulin resistance and argues against SCD1 inhibition as a safe therapeutic target for the metabolic syndrome.
Key Words: atherosclerosis • diabetes mellitus • fatty acids • inflammation • obesity
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Introduction |
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The metabolic syndrome has become a leading health concern in developed countries. This syndrome is a collection of metabolic abnormalities that include abdominal obesity, hypertension, insulin resistance, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol levels.1–3 Recently, the metabolic syndrome has been shown to be a predictor of atherosclerotic cardiovascular disease (CVD) in humans.1–3 Therefore, potential therapeutic targets for the metabolic syndrome are actively being pursued to combat CVD, and stearoyl-coenzyme A desaturase 1 (SCD1) has come to the forefront in this pursuit.4–6 By catalyzing the conversion of long-chain saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), SCD1 promotes multiple aspects of the metabolic syndrome. In fact, mice lacking SCD1 are largely protected against diet-induced and genetically induced obesity,7–11 hepatic steatosis,11–14 hypertriglyceridemia,15,16 and insulin resistance.7,9,17,18
Clinical Perspective p 1475
Because mice lacking SCD1 have severely impaired hepatic neutral lipid biosynthesis,19 we hypothesized that SCD1 inhibition would diminish the hepatic production of MUFA-rich cholesteryl esters (CEs) and triglycerides (TG), thereby protecting against hyperlipidemia and atherosclerosis. To test this idea, we used antisense oligonucleotide (ASO)–mediated knockdown of SCD1 in a well-characterized mouse model of hyperlipidemia and atherosclerosis. The results from this study demonstrate that the metabolic syndrome can be dissociated from atherosclerosis in mice and warn that SFA accumulation seen with SCD1 inhibition can promote inflammation and atherosclerosis.
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Methods |
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A detailed description of the materials and methods used is provided in the online-only Data Supplement.
Experimental Design
Male apolipoprotein (Apo) B100-only, low density lipoprotein (LDL) receptor (LDLr)–deficient (LDLr–/–Apob100/100) mice were used in this study. These mice were chosen on the basis of previous reports documenting their "human-like" lipoprotein profile,20 atherosclerosis susceptibility,20 and responsiveness to dietary fatty acids.21 All mice were on a mixed background (
75% C57BL/6 and 25% 129Sv/Jae). At 6 weeks of age, the mice were switched from a diet of rodent chow to 1 of 2 synthetic diets containing 12% of energy as SFA-enriched fat (palm oil) or MUFA-enriched fat (oleinate-enriched safflower oil) with 0.1% (wt/wt) cholesterol added. Table I of the online-only Data Supplement provides a complete analysis of the dietary fatty acid composition. In conjunction with diet, mice were injected biweekly with saline, 25 mg/kg of a nontargeting ASO (control ASO; 5'-TCCCATTTCAGGAGACCTGG-3'), or 25 mg/kg of an ASO targeting the knockdown of SCD1 (SCD1 ASO; 5'-GCTCTAATCACCTCAGAACT-3'). These phosphorothioate-modified ASO compounds were generously provided by ISIS Pharmaceuticals, Inc (Carlsbad, Calif). Body weight was measured weekly, and food intake was measured at 4 and 8 weeks of diet/ASO treatment. All experimental animals were killed after 20 weeks of parallel dietary and ASO treatment. All mice were maintained in a pathogen-free animal facility, and experimental protocols were approved by the institutional animal care and use committee at the Wake Forest University School of Medicine.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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SCD1 ASO Treatment Inhibits Hepatic and Adipose SCD1 Function
After 20 weeks of ASO treatment, liver and adipose SCD1 mRNA levels were reduced by 99% and 83% to 94%, respectively (Figure 1A). Furthermore, SCD1 protein expression was undetectable by Western blot in both liver and adipose tissue (Figure 1B). Hepatic SCD1 activity was reduced by >95% after 20 weeks of treatment (Figure 1C). After only 4 weeks of ASO treatment, hepatic SCD1 protein and activity levels were reduced by >90% (data not shown). Importantly, SCD1 protein expression in skeletal muscle and skin was not altered by 20 weeks of SCD1 ASO treatment (data not shown). This tissue-specific pattern of knockdown is likely due to the intrinsic pharmacokinetic properties of ASOs and has previously been described with other ASO compounds of similar chemistry in mice.22,23
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), a nontargeting control ASO (
), or SCD1 ASO (
). A, Relative quantification of SCD1 mRNA levels in the liver or adipose tissue was conducted by real-time quantitative polymerase chain reaction and normalized to cyclophilin. Data shown represent pooled RNA samples with 5 mice per group. B, Western blot analysis of SCD1 and protein disulfide isomerase (PDI) protein expression in liver and adipose tissue microsomes (n=3 per group). C, Hepatic SCD1 activity. Data represent the mean±SEM from 5 mice per group, and differences between the control ASO and SCD1 ASO groups were highly significant (P<0.01). AU indicates arbitrary units.
SCD1 Inhibition Prevents Diet-Induced Obesity and Insulin Resistance in Hyperlipidemic Mice
In agreement with previous reports,7–11 SCD1 inhibition prevented diet-induced obesity in LDLr–/–Apob100/100 mice. (Figure 2A through 2C). Epididymal fat pad mass was reduced by 85% on the saturated diet and 80% on the MUFA-rich diet compared with control ASO–treated mice (Figure 2C), which could not be explained by reductions in food intake (Figure 2D) and may result from the previously described role of SCD1 in energy expenditure.7,8,24 After only 4 weeks of treatment, fasting insulin levels were significantly lower in SCD1 ASO–treated mice (Figure 2E). In parallel, SCD1 inhibition significantly improved glucose tolerance (Figure 2F) and insulin tolerance (Figure 2G). Importantly, the effects of SCD1 inhibition on adiposity and insulin resistance could not be reversed by dietary MUFA supplementation (Figure 2). Collectively, these data support the notion that ASO-mediated inhibition of SCD1 is efficacious in the prevention of diet-induced obesity and insulin resistance.10,17
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in line graphs). Photographs (A), body weights (B), and epididymal fat pad mass (C) of mice after 20 weeks of diet and ASO treatment. Data in B and C represent the mean±SEM from 8 to 15 mice per group; values not sharing a common superscript differ significantly (P<0.05). D, Food intake was measured after 8 weeks of diet and ASO treatment. No significant differences were detected. E, Fasting plasma insulin levels were measured after 4 weeks of diet and ASO treatment. Data represent the mean±SEM from 5 mice per group; values not sharing a common superscript differ significantly (P<0.05). Glucose tolerance tests (F) and insulin tolerance tests (G) were performed after 16 weeks of diet and ASO treatment. Data shown in F and G represent the mean±SEM from 5 mice per group. *Significantly different from the control ASO group within each diet group (P<0.05).
SCD1 Inhibition Promotes Atherosclerosis
En face morphometric analysis showed that SCD1 ASO–treated mice had 2.7-fold (SFA diet) and 2.6-fold (MUFA diet) increases in total aortic lesion area (Figure 3B) compared with control ASO–treated mice. Interestingly, this SCD1 ASO–driven augmentation of atherosclerotic lesion area seemed to be regional in nature (Figure 3A and 3C). When the control and SCD1 ASO groups were compared, no significant differences were found in en face lesion area in the aortic arch (Figure 3C). However, modest increases were found in the thoracic aorta lesion area and highly significant increases in the abdominal aorta lesion area when SCD1 was inhibited (Figure 3C). In fact, SCD1 inhibition caused a striking 5-fold (MUFA diet) to 7-fold (SFA diet) increase in abdominal aortic lesion area, where >70% of the abdominal aorta was covered with lesion in SCD1-inhibited mice (Figure 3A and 3C). Biochemical analysis of the complete set (n=8 to 15 per group) of whole aortas from this study revealed that SCD1 inhibition resulted in significant increases in both free and esterified cholesterol compared with either saline- or control ASO–treated mice (Figure 3D and 3E). Furthermore, SCD1 inhibition resulted in enrichment of SFA and depletion of MUFA in aortic CE and TG (Figure 3F and 3G). Although less dramatic than the effects seen in CE (Figure 3F) and TG (Figure 3G), aortic phospholipid was likewise significantly depleted of MUFA (Figure 3H), and desaturation indexes (16:1/16:0 and 18:1/18:0) were significantly reduced with SCD1 inhibition (data not shown). Importantly, dietary MUFA did not prevent SCD1 ASO–mediated promotion of aortic atherosclerosis (Figure 3). In agreement with en face (Figure 3A through 3C) and biochemical (Figure 3D and 3E) analyses, histological evaluation of cross sections from the proximal aorta revealed that SCD1 inhibition promoted the accumulation of cholesterol clefts and necrotic core formation (online-only Data Supplement Figure I). Similar histological lesion characteristics were seen in thoracic and abdominal aortic sections (data not shown). Collectively, these data provide evidence that SCD1 inhibition promotes SFA- and cholesterol-rich atherosclerotic lesion formation in LDLr–/–Apob100/100 mice.
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SCD1 Inhibition Promotes SFA Enrichment of Plasma Lipoproteins
In agreement with previous reports,1–3 our results showed that SCD1 inhibition prevented diet-induced hypertriglyceridemia (Figure 4A). In contrast, total plasma cholesterol was only modestly (1861 mg/dL in control ASO group versus 1241 mg/dL in SCD1 ASO group) reduced after 20 weeks of the SFA diet but was not significantly altered under any other conditions (Figure 4B). When lipoprotein cholesterol distribution was analyzed, we discovered that SCD1 inhibition decreased very low-density lipoprotein (VLDL) cholesterol, had no effect on LDL cholesterol levels, and significantly reduced HDL cholesterol (Figure 4C and 4D). These SCD1 ASO–driven reductions in VLDL and HDL cholesterol levels were accompanied by reductions in plasma ApoE and ApoAI, whereas plasma ApoB and lecithin:cholesterol acyltransferase were not altered by SCD1 inhibition (Figure 4G). Furthermore, VLDL particles were significantly smaller in SCD1 ASO–treated mice (Figure 4F), possibly because of depletion of TG-rich core (Figure 4A). However, LDL and HDL particle sizes were not altered by SCD1 ASO treatment (Figure 4F). Finally, SCD1 inhibition resulted in reductions of MUFAs with highly significant enrichments of SFAs in LDL-CE and similar but less impressive fatty acid shifts in HDL-CE (Figure 4E). Collectively, SCD1 inhibition resulted in dramatic alterations in plasma lipoprotein metabolism, including diminished plasma TG, VLDL cholesterol, HDL cholesterol, VLDL size, and ApoE and ApoAI levels and striking enrichment of plasma lipoproteins with SFAs. Importantly, none of the SCD1 ASO–driven alterations in lipoprotein metabolism were prevented by dietary MUFAs (Figure 4A, 4B, and 4E and data not shown).
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SCD1 Inhibition Prevents Diet-Induced Steatosis
It has been well documented that mice lacking SCD1 are protected against hepatic steatosis under a variety of conditions.1,4–7 In addition to confirming these reports, we set out to characterize hepatic cholesterol metabolism in SCD1 ASO–treated mice because cholesterol-rich atherogenic ApoB-containing lipoproteins are believed to originate from the liver.25 As expected, SCD1 inhibition resulted in striking reductions in hepatic steatosis (online-only Data Supplement Figure IIA), manifested as a 93% reduction in hepatic TG concentration and an 81% reduction in hepatic CE concentration (online-only Data Supplement Figure IIB) compared with control ASO–treated mice. This reduction in hepatic triglycerides mass may be partially a result of a reduction in SREBP1c protein expression (online-only Data Supplement Figure IIF), with parallel downregulation of SREBP1c target genes (online-only Data Supplement Figure IIE), including fatty acid synthase, acetyl-coenzyme A carboxylase, and mitochondrial glycerol-3-phosphate acyltransferase. Quite unexpectedly, hepatic free cholesterol concentration was significantly increased by 1.5-fold (SFA diet) or 2.4-fold (MUFA diet; data not shown) when SCD1 was inhibited (online-only Data Supplement Figure IIB). The hepatic free cholesterol increase seen with SCD1 ASO treatment was accompanied by compensatory downregulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, upregulation of Cyp7
1, but normal ATP-binding cassette protein G5 (ABCG5) mRNA expression (online-only Data Supplement Figure IIE). Protein expression of ABCG5 also was not altered by SCD1 ASO treatment (online-only Data Supplement Figure IIF). Interestingly, ACAT2 protein expression was slightly increased with SCD1 ASO treatment (online-only Data Supplement Figure IIF) without corresponding changes in mRNA expression (data not shown), indicating posttranscriptional regulation. During isolated liver perfusion, it was found that SCD1 inhibition did not significantly alter the secretion rate of TG, CE, free cholesterol, or phospholipids (online-only Data Supplement Figure IIC). A trend was found toward a decrease in TG secretion rate with SCD1 ASO treatment, but it was not statistically significant (online-only Data Supplement Figure IIC). A closer look at the fatty acid composition of hepatic CE, TG, and phospholipids revealed that SCD1 inhibition promoted the enrichment of SFA into hepatic CE and TG but not phospholipids (online-only Data Supplement Figure IID). None of the SCD1 ASO–driven alterations in hepatic lipid metabolism were prevented by dietary MUFAs (data not shown). Collectively, these data support previous observations7,8,10,12,14,17 that SCD1 inhibition is efficacious in the prevention of hepatic steatosis, but surprisingly, augmented free cholesterol concentrations also were present.
SCD1 Inhibition Exacerbates Toll-Like Receptor 4–Driven Proinflammatory Response in Macrophages
Macrophages can play a pivotal role in the pathogenesis of atherosclerosis through multiple mechanisms, including their well-known role in producing atherogenic cytokine signals.26 It has been demonstrated that SFAs promote inflammatory cytokine secretion in macrophages through a toll-like receptor 4 (TLR4)–dependent mechanism.27–30 Because SCD1 inhibition resulted in striking SFA enrichment of LDL-CE (Figure 4E), we hypothesized that macrophage lipids may likewise become enriched in SFAs, thereby enhancing TLR4-dependent proinflammatory cytokine secretion. We found that in vivo SCD1 ASO treatment for 6 weeks reduced SCD1 mRNA and protein expression by >90% and >50%, respectively, in isolated macrophages (Figure 5A). In addition, macrophages isolated from SCD1 ASO–treated mice had a significantly decreased 16:1/16:0 ratio and an increased proportion of linoleic acid (18:2; n=6) in isolated phospholipids (Figure 5B). Similar effects were observed in neutral lipids, with SCD1 inhibition resulting in significant decreases in 16:1/16:0 and 18:1/18:0 ratios (data not shown). Interestingly, when macrophages isolated from SCD1 ASO–treated mice were challenged with a TLR4 agonist (10 ng/mL Kdo2-lipid A), marked hypersensitivity was apparent (Figure 5C and 5D). In support of this, SCD1 inhibition resulted in augmented TLR4-driven proinflammatory gene expression (Figure 5C) and cytokine secretion (Figure 5D) in isolated macrophages, although basal expression (ie, the absence of TLR4 ligand) of inflammatory cytokines was not significantly different between macrophages isolated from control- and SCD1 ASO–treated mice (data not shown). When we examined the expression of key proteins involved in TLR4-dependent signal transduction,31,32 we found a slight reduction in TLR4 expression, no change in MyD88, and a slight reduction in CD14 in SCD1-inhibited macrophages (Figure 5F). Furthermore, canonical TLR4-MyD88–dependent activation of mitogen-activated protein kinases, phosphorylation of inhibitor 
-kinase /β, and downstream degradation of inhibitory B-kinase was not different between control- and SCD1 ASO–treated macrophages (Figure 5E). However, the TLR4-MyD88–independent driven tyrosine phosphorylation of STAT1, a well-known interferon-β–dependent event,33 was markedly elevated in SCD1-inhibited macrophages (Figure 5E).
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Discussion |
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Although the presence of the metabolic syndrome seems to be associated with atherosclerotic CVD outcomes in humans,1–3 dissociation of the two has previously been reported.34 Results from this study provide evidence that the metabolic syndrome can be completely dissociated from atherosclerosis in mice. That is, in the extreme case of leanness and insulin sensitivity induced by SCD1 ASO treatment, atherosclerosis progressed independently. Results from this study support the notion7–18 that SCD1 inhibitors may be efficacious in preventing many aspects of the metabolic syndrome (diet-induced obesity, hepatic steatosis, insulin resistance, hypertriglyceridemia), but perhaps at the expense of the artery wall. To help explain this unexpected finding, we propose a working model in which SCD1 inhibitors promote atherosclerosis (Figure 6). Briefly, we believe that inhibition of SCD1 in the liver results in secretion of VLDL particles that are highly enriched in SFA-rich CE, giving rise to SFA-CE–rich LDL particles. These SFA-CE–rich LDL particles deliver SFA to macrophages, which also have diminished SCD1 expression, resulting in accumulation of SFA in macrophages, enhanced TLR4-driven tyrosine phosphorylation of STAT1, and ultimately enhanced inflammatory cytokine secretion. This proinflammatory phenotype thereby promotes atherosclerosis in a hyperlipidemic setting.
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In support of this model, a role for SCD1 in protecting against another inflammation-driven disease (dextran sulfate sodium–induced colitis) was recently reported.35 In this report, Chen et al35 elegantly demonstrated that mice lacking SCD1 had elevated dextran sulfate sodium– and bacteria-driven inflammatory gene expression and exaggerated colitis, findings analogous to our results. This study, as well as ours, supports the long-standing notion that SFAs are potent proinflammatory molecules.27–30 Hence, one of the key roles of SCD1 may be to suppress inflammation by preventing excessive accumulation of SFAs themselves and downstream metabolites such as stearoyl-lysophosphatidylcholine35 and ceramide.36 Importantly, this study now joins several recent reports that have demonstrated unexpected harmful consequences of inhibiting SCD1.18,35,37
The molecular mechanism(s) by which SCD1 inhibition promotes atherosclerosis (Figure 3), inflammatory colitis,35 frank diabetes,18 and cholestasis37 have not been clearly elucidated. More work is needed to address these unexpected outcomes if SCD1 inhibitors are to be pursued as CVD therapeutics in humans. In addition to SCD1 inhibitors, TLR4 antagonists have been suggested as potential CVD therapeutics, but whether TLR4 plays a role in atherosclerosis in humans has been a matter of intense debate.38–40 Indeed, more work is needed to investigate whether TLR4 is necessary for SFA-dependent induction of diseases such as atherosclerosis and the other diverse pathologies associated with SCD1 inhibition18,35,37 (Figure 3). Performing SCD1 inhibition studies in TLR4-deficient mice will no doubt provide useful insight into the necessity of TLR4 in promoting both endogenous and dietary SFA-driven atherosclerosis and other inflammatory diseases.
One potential unifying mechanism driving the multiple pathologies seen under conditions of SCD1 deficiency may involve the previously documented function of SCD1 in modulating the formation of cholesterol- and SFA-rich membrane microdomains, better known as "lipid rafts." It has previously been shown that overexpression of SCD1 in macrophages results in decreased abundance of liquid-ordered domains or lipid rafts.41 This finding correlates well with the recent report that mice lacking SCD1 in a leptin-deficient background have massive accumulation of free cholesterol and SFA in pancreatic β cells.18 Our study further supports this idea, given that SCD1 inhibition resulted in accumulation of free cholesterol and SFA in the liver (online-only Data Supplement Figure IIB and IID), aorta (Figure 3E through 3H), and isolated macrophages (data not shown). Collectively, these data suggest that SCD1 may play a crucial role in limiting accumulation of lipids (cholesterol and SFAs) known to segregate into membrane liquid-ordered domains, which could potentially alter membrane-associated signal transduction.
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Conclusions |
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The present study demonstrates that inhibition of SCD1 protects against development of the metabolic syndrome but may promote atherosclerosis. These results do not support the idea that obesity and insulin resistance are causatively linked to atherosclerosis and argue against SCD1 inhibition as a safe therapeutic target for treatment of CVD.
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Acknowledgments |
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We thank Rosanne Crooke, Mark Graham, and Richard Lee (ISIS Pharmaceuticals, Inc, Carlsbad, Calif) for providing the ASOs used in this study. We also thank James Ntambi, Alan Tall, Helen Hobbs, Joachim Herz, and Jay Horton for providing the antibodies used in this study.
Sources of Funding
This work was supported by grants from the National Institutes of Health (NIH-P01-HL49373 to Drs Rudel and Parks), the American Heart Association (AHA postdoctoral fellowship 0625400U to Dr Brown), and the Howard Hughes Medical Institute (Gilliam Fellowship to T. Nguyen).
Disclosures
None.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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1. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008; 28: 629–636.
2. Kahn R. Metabolic syndrome: is it a syndrome? Does it matter? Circulation. 2007; 115: 1806–1810.
3. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005; 112: 2735–2752.
4. Cohen P, Ntambi JM, Friedman JM. Stearoyl-CoA desaturase-1 and the metabolic syndrome. Curr Drug Targets Immune Endocr Metabol Disord. 2003; 3: 271–280.[CrossRef][Medline] [Order article via Infotrieve]
5. Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev. 2005; 6: 169–174.[CrossRef][Medline] [Order article via Infotrieve]
6. Miyazaki M, Ntambi JM. Role of stearoyl-coenzyme A desaturase in lipid metabolism. Prostaglandins Leukot Essent Fatty Acids. 2003; 68: 113–121.[CrossRef][Medline] [Order article via Infotrieve]
7. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A. 2002; 99: 11482–11486.
8. Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002; 297: 240–243.
9. Macdonald ML, Singaraja RR, Bissada N, Ruddle P, Watts R, Karasinska JM, Gibson WT, Fievet C, Vance JE, Staels B, Hayden MR. Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice. J Lipid Res. 2008; 49: 217–229.
10. Jiang G, Li Z, Liu F, Ellsworth K, Dallas-Yang Q, Wu M, Ronan J, Esau C, Murphy C, Szalkowski D, Bergeron R, Doebber T, Zhang BB. Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest. 2005; 115: 1030–1038.[CrossRef][Medline] [Order article via Infotrieve]
11. Miyazaki M, Dobrzyn A, Sampath H, Lee SH, Man WC, Chu K, Peters JM, Gonzalez FJ, Ntambi JM. Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferators-activated receptor-alpha. J Biol Chem. 2004; 279: 35017–35024.
12. Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, Soukas AA, Kahn CR, Ntambi JM, Socci ND, Friedman JM. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest. 2004; 113: 414–424.[CrossRef][Medline] [Order article via Infotrieve]
13. Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim HJ, Ntambi JM. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J Biol Chem. 2004; 279: 25164–25171.
14. Miyazaki M, Flowers MT, Sampath H, Chu K, Otzelberger C, Liu X, Ntambi JM. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab. 2007; 6: 484–496.[CrossRef][Medline] [Order article via Infotrieve]
15. Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, Lusis AJ, Stalenhoef AF, Stoehr JP, Hayden MR, Ntambi JM. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res. 2002; 43: 1899–1907.
16. Chu K, Miyazaki M, Man WC, Ntambi JM. Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation. Mol Cell Biol. 2006; 26: 6786–6798.
17. Gutierrez-Juarez R, Pocai A, Mulas C, Ono H, Bhanot S, Monia BP, Rosetti L. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006; 116: 1686–1695.[CrossRef][Medline] [Order article via Infotrieve]
18. Flowers JB, Rabglia ME, Schueler KL, Flowers MT, Lan H, Keller MP, Ntambi JM, Attie AD. Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes. 2007; 56: 1228–1239.[CrossRef][Medline] [Order article via Infotrieve]
19. Miyazaki M, Kim YC, Gray-Keller MP, Attie AD, Ntambi JM. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem. 2000; 275: 30132–30128.
20. Veniant MM, Sullivan MA, Kim SK, Ambroziak P, Chu A, Wilson MD, Hellerstein MK, Rudel LL, Walzem RL, Young SG. Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100. J Clin Invest. 2000; 106: 1501–1510.[Medline] [Order article via Infotrieve]
21. Bell TA III, Kelley K, Wilson MD, Sawyer JK, Rudel LL. Dietary fat-induced alterations in atherosclerosis are abolished by ACAT2-deficiency in ApoB100 only, LDLr–/– mice. Arterioscler Thromb Vasc Biol. 2007; 27: 1396–1402.
22. Levin AA, Yu RZ, Geary RS. Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. In: Antisense Drug Technology. 2nd ed. Boca Raton, Fla: CRC Press; 2008.
23. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 2007; 282: 22678–22688.
24. Lee SH, Dobrzyn A, Dobrzyn P, Rahman SM, Miyazaki M, Ntambi JM. Lack of stearoyl-CoA desaturase 1 upregulates basal thermogenesis but causes hypothermia in a cold environment. J Lipid Res. 2004; 45: 1674–1682.
25. Rudel LL, Haines J, Sawyer JK, Shah R, Wilson MS, Carr TP. Hepatic origin of cholesteryl oleate in coronary artery atherosclerosis in African green monkeys: enrichment by dietary monounsaturated fat. J Clin Invest. 1997; 100: 74–83.[Medline] [Order article via Infotrieve]
26. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002; 91: 281–291.
27. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006; 116: 3015–3025.[CrossRef][Medline] [Order article via Infotrieve]
28. Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 2001; 276: 16683–16689.
29. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007; 27: 84–91.
30. Renier G, Skamene E, DeSanctis J, Radzioch D. Dietary n-3 polyunsaturated fatty acids prevent the development of atherosclerotic lesions in mice: modulation of macrophage secretory activities. Arterioscler Thromb. 1993; 13: 1515–1524.
31. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004; 16: 3–9.[CrossRef][Medline] [Order article via Infotrieve]
32. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B. CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005; 6: 565–570.[CrossRef][Medline] [Order article via Infotrieve]
33. Thomas KE, Galligan CL, Newman RD, Fish EN, Vogel SN. Contribution of interferon-beta to the murine macrophage response to the toll-like receptor 4 agonist, lipopolysaccharide. J Biol Chem. 2006; 281: 31119–31130.
34. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006; 116: 1813–1822.[CrossRef][Medline] [Order article via Infotrieve]
35. Chen C, Shah YM, Morimura K, Krausz KW, Miyazaki M, Richardson TA, Morgan ET, Ntambi JM, Idel JR, Gonzalez FJ. Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab. 2008; 7: 135–147.[CrossRef][Medline] [Order article via Infotrieve]
36. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated fat-, and obesity-induced insulin resistance. Cell Metab. 2007; 5: 167–179.[CrossRef][Medline] [Order article via Infotrieve]
37. Flowers MT, Groen AK, Oler AT, Keller MP, Choi Y, Schueler KL, Richards OC, Lan H, Miyazaki M, Kuipers F, Kendziorski CM, Ntambi JM, Attie AD. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet. J Lipid Res. 2006; 47: 2668–2680.
38. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002; 347: 185–192.
39. Yang IA, Holloway JW, Ye S. TLR4 Asp299Gly polymorphism in not associated with coronary artery stenosis. Atherosclerosis. 2003; 170: 187–190.[CrossRef][Medline] [Order article via Infotrieve]
40. Netea MG, Hijmans A, van Wissen S, Smilde TJ, Trip MD, Kullberg BJ, de Boo T, Van der Meer JW, Kastelein JJ, Stalenhoef AF. Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolemia. Eur J Clin Invest. 2004; 34: 94–99.[CrossRef][Medline] [Order article via Infotrieve]
41. Sun Y, Hao M, Luo Y, Liang CP, Silver DL, Cheng C, Maxfield FR, Tall AR. Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure. J Biol Chem. 2003; 278: 5813–5820.
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The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.793182/DC1.
Related Article:
Circulation 2008 118: 1403-1404.
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