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* Departamento de Bioquímica y Biología Molecular y Celular and Patología Animal, Facultad de Veterinaria, Universidad de Zaragoza, E-50013 Zaragoza, Spain and ** Nutrigenomics Research Group, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
2 To whom correspondence should be addressed. E-mail: josada{at}unizar.es.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • conjugated linoleic acid • apolipoprotein • high density lipoproteins • atherosclerosis • paraoxonase
Epidemiological studies show that an inverse relation exists between HDL cholesterol (HDL-C)3 concentrations and the risk of coronary heart disease (CHD) (1). The results of clinical trials suggest that high HDL-C levels help prevent cardiovascular events (2). However, current knowledge is insufficient to warrant the setting of target levels (3).
The antiatherogenic properties of regular HDL particles have been ascribed to their anti-inflammatory, antioxidant and profibrinolytic activities, and to their ability to promote cholesterol efflux from cells in artery walls (4). HDL particles are a heterogeneous class of lipoproteins with subtypes identified on the basis of their density, electrophoretic mobility, particle size, and apolipoprotein composition (5). There is growing evidence to suggest that not all HDL particles share the same biological properties. This may be due to these molecules bonding with different apolipoproteins, or to enzymes and transfer proteins that modulate HDL particle composition, fate, and function. For example, HDL particles enriched in apolipoprotein (apo) A-I or A-IV are considered antiatherogenic (6,7), whereas HDL-apoA-II is associated with proatherogenic effects (8). Thus, the HDL-C concentration on its own may not adequately reflect the consequences of the presence of different lipoparticles.
The term "conjugated linoleic acid" (CLA) refers to a group of positional and geometric isomers of linoleic acid. The cis-9, trans-11-CLA (c9,t11-CLA) isomer is the most abundant in meat and dairy products (9), although the trans-10, cis-12-CLA (t10,c12-CLA) isomer appears in almost equal concentrations in most processed CLA-containing foods and supplements (10). Multiple biological effects have been ascribed to CLA including the control of body composition and energy metabolism, the modulation of the immune response, lipid metabolism, and insulin resistance (11–16). Several authors reported that the different CLA isomers have different effects on lipid metabolism in animals and humans (17–19). Notably, t10,c12-CLA increases HDL-C concentrations but also promotes atherosclerosis (20,21), suggesting that the HDL molecules produced are not fully effective in preventing this disease.
The aim of the present work was to determine how the different CLA isomers modify the relations among HDL composition, hepatic lipid metabolism, and atherosclerotic lesions in apoE-deficient mice. These well-characterized mice spontaneously develop atherosclerosis with features similar to those observed in humans (22).
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The mice were fed the different experimental semipurified diets for 12 wk. All three diets were isocaloric and isonitrogenous;4 fat provided 30% of the energy intake. The control diet contained 1.0% (wt/wt) linoleic acid, whereas the others contained an equivalent amount of either c9,t11-CLA or t10,c12-CLA, as previously described (19,23). All diets were prepared by Unilever and stored in an N2 atmosphere at –20°C. Fresh food was provided daily. The study protocol was approved by the Ethics Committee for Animal Research of the University of Zaragoza.
Biochemical determinations. At the end of the 12-wk period the mice were killed by suffocation with CO2. Blood was drawn from the heart, and the livers of all mice were quickly frozen in liquid N2. Plasma total triglyceride (TG) and cholesterol concentrations were determined by microtiter assay (Triglyceride Kit 2016647, Roche Diagnostics and Infinity Cholesterol Reagent Kit 401-25P, Sigma Chemical).
Paraoxonase was determined as aryl esterase activity, as previously described (24); the results were expressed as µmol/(min·L) of hydrolyzed phenyl acetate. ApoA-I, A-II, and C-III were quantified by ELISA using specific polyclonal antibodies (Biodesign) as previously described (25). All samples were analyzed on the same day; all assays were performed in triplicate. The intra-assay CV was <4% in all cases.
Histological analysis. The bases of the mouse hearts were collected and processed for aortic cross-sectional analysis as previously described (26). A sample of liver from each mouse was stored in neutral formaldehyde and embedded in paraffin wax. Sections (4 µm) were stained with hematoxylin and eosin and observed using a Nikon microscope.
Gel filtration chromatography. Fast protein liquid chromatography (FPLC) employing a Superose 6B column (Amersham Biosciences) was used to separate the lipoproteins as previously described (26). Fractions containing apoA-I were considered as representative of regular HDL, and the cholesterol content was estimated using the Amplex® Red A12216 cholesterol assay (Molecular Probes) following the manufacturer's instructions. Nonesterified cholesterol was determined using the same method but omitting the cholesterol esterase. The intensity of fluorescence was measured with a microplate reader (SPECTRAfluor Plus, TECAN) at 595 nm using an excitation wavelength of 550 nm. The results were linear from 38 nmol/L to 10 µmol/L cholesterol.
Western blotting. The plasma and FPLC fractions were loaded onto 12% SDS-PAGE gels, electrophoresed, and transferred as previously described (27). Protein bands were detected using rabbit polyclonal anti-mouse apoA-IV antibodies (Santa Cruz Biotechnology). Paraoxonase 1 (PON1) protein bands were detected using a rabbit polyclonal antibody raised against a mouse oligopeptide (CYKNHRSSYQTRLNAFREVTP) following standard immunization protocols (28).
RNA preparation and analysis. Liver RNA was isolated using Trigent reagent MRC following the manufacturer's instructions. Northern blot analysis was performed as previously described (24). The mouse clones for pon-1 (4158951 IMAGE Clone) and apoa5 (4196296 IMAGE Clone) were obtained from MGC Geneservice. The probes used were as follows: Pon-1 (24), apoa1 (24), apoa5, a 1805-bp EcorI/XbaI fragment, apoc3, a 410-bp XbaI/XhoI corresponding to the fourth exon of apoc3, an apoa4 probe, and a 321-bp BamHI/XhoI fragment corresponding to the third exon of apoa4. A mouse ß-actin fragment (24) was used to normalize the amount of RNA. Labeling and quantification were performed as previously described (24).
Equal amounts of RNA from each mouse were used in quantitative real-time RT-PCR analyses. First-strand cDNA synthesis and the PCR reactions were performed using the SuperScript III Platinum Two-Step qRT-PCR Kit with SYBR Green (Invitrogen), according to the manufacturer's instructions. The following primers were used in real-time PCR: for abca1: sense, 5'-GGT TTG GAG ATG GTT ATA CAA TAG TTG T-3', antisense 5'-TTC CCG GAA ACG CAA GTC-3'; for apoa2: sense, 5'-TGC TCG CAA TGG TCG CAC TG-3', antisense 5'-TCT GAG GTC TTG GCC TTC TCC ACC-3'; for endothelial lipase: sense, 5'-TCC TGC ATA CCT ACA CGC TGT C-3', antisense, 5'-GTC AAT GTG ACC CAC AGG CA-3'; for hepatic lipase: sense, 5'-TGA CCT GCA GAG CAT CGG CTT C-3', antisense, 5'-TCT TGC CTG ACC GGT CCT TG-3'; for sr-b1: sense, 5'-GGC TGC TGT TTG CTG CG-3', antisense, 5'-GCT GCT TGA TGA GGG AGG G-3'; and for ß-actin: sense, 5'-CTG ACT GAC TAC CTC ATG AAG ATC CT-3', antisense, 5'-CTT AAT GTC ACG CAC GAT TTC C-3'. Real-time PCR reactions were performed in an ABI PRISM 7700 Sequence Detector (Applied Biosystems). The relative amount of all mRNAs was calculated using the comparative 2–
Ct method. ß-Actin mRNA was used as the invariant control.
Statistical analysis.
The results are expressed as means ± SD. Comparisons were made using 1-way ANOVA and the Tukey-Kramer multiple comparison test (post hoc) when the distribution of the variables was normal. When the variables did not show such a distribution (according to the Shapiro-Wilks test) or failed to show homology of variance, comparisons were made using the Mann-Whitney U test. Correlations between variables were sought using the Pearson correlation test. All calculations were performed using SPSS version 11.0 software. Significance was set at P 
0.05.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Interestingly, the t10,c12-CLA diet was associated with a markedly different distribution of apoA-I and ApoA-II in the HDL subfractions compared with the control and c9,t10-CLA diets. ApoA-I was reduced, whereas the apoA-II concentration was increased in the cholesterol-rich HDL fractions 16–21. Further, the peaks of these apolipoproteins were no longer superimposed, indicating that the appearance of HDL-A-II was due to the t10,c12-CLA–enriched diet. In contrast, almost all the apoA-I was present in the cholesterol-poor HDL particles (fractions 22–26) in mice after consumption of the t10,c12-CLA diet. These results indicate that important remodeling of HDL particles occurs after the administration of the different CLA isomers.
Although apoC-III is not exclusively bound to HDL, its plasma concentration was determined to explain the variable TG concentrations after the administration of the different CLA isomers. The t10,c12-CLA diet induced hypertriglyceridemia (46.5 ± 6.0 compared with 17.8 ± 0.9 mmol/L for control group; P < 0.05). In contrast, the c9,t11-CLA diet reduced the TG concentration (13.3 ± 1.5 compared with 17.8 ± 0.9 mmol/L for the control group). Compared with the controls, plasma apoC-III concentrations were significantly lower in the c9,t11-CLA group and significantly higher in the t10,c12-CLA group (Table 2). Indeed, plasma apoC-III concentrations correlated with plasma TG (r = 0.722, P < 0.001).
Surprisingly, there was a significant, positive association (r = 0.883, P < 0.001) between plasma apoA-II and apoC-III. To further explore this association, apoC-III was determined in the cholesterol-rich and cholesterol-poor HDL fractions. ApoC-III levels were increased in the high cholesterol HDL fraction in mice fed the t10,c12-CLA diet, reflecting the redistribution of HDL-apoA-II (Fig. 1C). HDL-apoA-IV composition was not altered by the dietary intervention (data not shown).
Paraoxonase concentrations. A progressive reduction in serum PON-1 levels occurred in mice after consumption of the c9,t11-CLA and t10,c12-CLA diets (Fig. 2A). Similarly, the hepatic expression of pon-1 mRNA was significantly reduced by the c9,t11-CLA diet and to an even greater extent by the t10,c12-CLA diet (Fig. 2B). Despite these alterations, the aryl esterase activity of PON-1 was not affected (data not shown).
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The t10,c12-CLA diet also reduced paraoxonase expression, which may be related to apoA-II overexpression (29). In the present study, the plasma PON-1 concentration and hepatic mRNA were reduced by both CLA diets, although more so by the t10,c12-CLA regimen. There were no differences in the aryl esterase activity of paraoxonase among any of the groups; however, the concentration of this enzyme was reduced in mice fed either of the CLA diets. The control mice had higher plasma PON-1 concentrations but with relatively reduced activity. This could be because linoleic acid, the main fatty acid of the control diet, is a potent destabilizing agent as well as a PON-1-arylesterase inhibitor (Ki = 3.8 mmol/L) (38). Because the final concentration of linoleic was 
12 µmol/L in the present assay, the possibility of enzyme inactivation seems the most plausible explanation for reduced activity in the control group. PON1 is differentially modulated by linoleic acid isomers at several levels. Thus, the CLA isomers caused a reduction in the protein mass brought about by variation in the liver mRNA levels. When linoleic acid was present, enzyme activity was substantially inactivated despite the fact that the enzyme concentration was twice that in the CLA-fed groups.
The apoa1/c3/a4/a5 gene cluster is jointly organized in the genome (39) and regulates lipoprotein metabolism and atherosclerosis (40). The c9,t11-CLA–rich diet increased apoa1, c3, a4, and a5 mRNA expression in the liver, but the t10,c12-CLA diet downregulated the expression of all of these genes with the exception of apoa4. Alterations in hepatic mRNA expression were partly reflected in plasma apolipoprotein levels, in particular those of apoA-I and apoA-IV. However, for C-III, there was an inverse correlation between hepatic expression and the plasma protein level, suggesting that it is regulated via another post-transcriptional CLA-mediated mechanism. Interestingly, a similar expression pattern was observed for apoc3 and apoa5, despite their opposing roles in plasma TG homeostasis (41). This suggests that the expression of apoa5 and apoc3 is coordinated at the mRNA level. These findings, plus the absence of any change in lipase expression, suggest that the phenotypic variations in HDL produced by CLA are a consequence of alterations in the apolipoprotein gene cluster and apoa2 gene expression, which ultimately affects lipid metabolism.
Other studies demonstrated that t10,c12-CLA is associated with hyperglycemia, hyperinsulinemia, and insulin resistance (23,42,43), reduced plasma leptin concentrations (42,43), and liver steatosis (43,44). In the present study, the mice fed t10,c12-CLA had hypertriglyceridemia, reduced apoA-I and increased apoA-II concentrations, significantly larger atherosclerotic lesions (Fig. 4), and a redistribution of apolipoproteins among the different HDL particles. This phenotype is similar to that of familial combined hyperlipidemia (FCHL) or metabolic syndrome (MS) (45). All of these traits of FCHL were described and characterized in apoA-II transgenic mice (30,46). The present results provide an unexplored mechanism that explains the link between hypertriglyceridemia and increased apoA-II levels via the existence of an increased presence of apoC-III in the same HDL particles. Further, these apolipoprotein changes can be explained by expression changes at the apoa1/c3/a4/a5 gene cluster and apoa2 gene, polymorphic variations that have been associated with FCHL (30). Together, these finding suggest that the administration of the t10,c12-CLA isomer to apoE-deficient mice provides an excellent FCHL and MS model for studying the relation between atherosclerosis, hepatic steatosis, and HDL apolipoprotein metabolism.
The dietary interventions had markedly different effects on the lipid content of the liver. The effects of CLA may be explained through interactions with a number of transcription factors, particularly the peroxisome proliferator-activated receptors (PPAR). Indeed both c9,t11-CLA and t10,c12-CLA are PPAR
and PPAR
ligands (42,47). PPAR activates lipolytic pathways and apolipoprotein production, ultimately reducing the fat content of the liver (48). Thus, c9,t11-CLA could promote PPAR activation, leading to reduced liver fat (Fig. 3) and increased apoa4 and a5 mRNA levels (Table 3). However, this does not explain the changes in apoa1, apoa2, c3 or abca1 mRNA levels, which are regulated by Foxo1 (49) or hepatic nuclear factor-4 (50). The t10,c12-CLA isomer promoted profound hepatic steatosis, an effect reported in other studies (42–44), reinforcing the notion that the absence of apoE does not modify the response to this isomer. This steatotic effect was attributed to increased hepatic TG, cholesterol, cholesterol esters, and free fatty acids (51), reflecting increased hepatic fatty acid synthesis (52). However, the mechanisms by which the liver becomes steatotic in response to t10,c12-CLA appear to be complex because t10,c12-CLA also induces ß-oxidation (53); this would not be associated with lipid accumulation. Indeed, the reduced apoc3 and apoa1 and increased apoa2 and apoa4 mRNA levels in this study (Table 3) suggest the involvement of PPAR, but this does not explain the changes in apoa5 or abca1 or fat accumulation (Fig. 3). The hepatic expression of abca1 was reduced with both CLA isomers, concordant with the liver X receptor- downregulation promoted by these isomers (23). Despite reduced hepatic abca1 mRNA expression, plasma cholesterol levels were modified in a CLA isomer–specific manner, suggesting that CLA also regulates phenotypic expression of this transporter at different levels, and that HDL-C levels are the result the action of many genes. Overall, these data indicate that for each gene involved, multiple transcription factors are required.
In conclusion, the present work shows that apoE-deficient mice fed t10,c12-CLA displayed characteristics of FCHL or MS. It would appear that simply measuring HDL-C levels is insufficient for determining the risk of cardiovascular disease due to HDL apolipoprotein changes. The results also suggest that diets rich in t10,c12-CLA may be proatherogenic, whereas those rich in c9,t11-CLA may be antiatherogenic.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; C, cholesterol; CHD, coronary heart disease, CLA, conjugated linoleic acid; c9,t11-CLA, cis-9, trans-11 CLA isomer; t10,c12-CLA, trans-10, cis-12 CLA isomer; FCHL, familial combined hyperlipidemia; FPLC, fast protein liquid chromatography; MS, metabolic syndrome; PON-1, paraoxonase 1; PPAR, peroxisome proliferator-activated receptors; TG, triglycerides.
4 The composition of the diet was (g/kg): cornstarch, 608; calcium caseinate, 158; fat, 123 (40% saturated, 33% monounsaturated and 27% polyunsaturated fatty acids); cellulose, 58.3; minerals, 40.7; vitamins, 11.7; and cholesterol, 1.5. The mineral and vitamin mixtures used were AIN-76 and AIN-76A respectively.
Manuscript received 8 August 2005. Initial review completed 24 September 2005. Revision accepted 9 November 2005.
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LITERATURE CITED |
|---|
|
TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Gordon D, Probstfield J, Garrison R, Neaton J, Castelli W, Knoke J, Jacobs D Jr, Bangdiwala S, Tyroler H. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8–15.
2. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–8.
3. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr., Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr., Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–39.
4. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov. 2005;4:193–205.[Medline]
5. von Eckardstein A, Huang Y, Assmann G. Physiological role and clinical relevance of high-density lipoprotein subclasses. Curr Opin Lipidol. 1994;5:404–16.[Medline]
6. Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift SM. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991;353:265–7.[Medline]
7. Stan S, Delvin E, Lambert M, Seidman E, Levy E. Apo A-IV: an update on regulation and physiologic functions. Biochim Biophys Acta. 2003;1631:177–87.[Medline]
8. Warden C, Daluiski A, Bu X, Purcell-Huynh D, Meester C, Shieh B, Puppione D, Gray R, Reaven G, et al. Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans. Proc Natl Acad Sci U S A. 1993;90:10886–90.
9. Parodi PW. Conjugated octadecadienoic acids of milk fat. J Dairy Sci. 1977;60:1550–3.
10. Gaullier JM, Berven G, Blankson H, Gudmundsen O. Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids. 2002;37:1019–25.[Medline]
11. Parodi PW. Conjugated linoleic acid and other anticarcinogenic agents of bovine milk fat. J Dairy Sci. 1999;82:1339–49.[Abstract]
12. Rudel LL. Atherosclerosis and conjugated linoleic acid. Br J Nutr. 1999;81:177–9.[Medline]
13. Pariza MW, Park Y, Cook ME. Mechanisms of action of conjugated linoleic acid: evidence and speculation. Proc Soc Exp Biol Med. 2000;223:8–13.
14. MacDonald HB. Conjugated linoleic acid and disease prevention: a review of current knowledge. J Am Coll Nutr. 2000;19:111S–8.
15. Belury MA. Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action. Annu Rev Nutr. 2002;22:505–31.[Medline]
16. Wahle KW, Heys SD, Rotondo D. Conjugated linoleic acids: are they beneficial or detrimental to health? Prog Lipid Res. 2004;43:553–87.[Medline]
17. Tricon S, Burdge GC, Kew S, Banerjee T, Russell JJ, Jones EL, Grimble RF, Williams CM, Yaqoob P, Calder PC. Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Am J Clin Nutr. 2004;80:614–20.
18. Terpstra AH. Effect of conjugated linoleic acid on body composition and plasma lipids in humans: an overview of the literature. Am J Clin Nutr. 2004;79:352–61.
19. De Roos B, Rucklidge G, Reid M, Pickard K, Navarro MA, Arbonés-Mainar JM, Guzman-García MA, Osada J, Browne J, et al. Divergent mechanisms of cis9, trans11- and trans10, cis12-conjugated linoleic acid affecting insulin resistance and inflammation in apolipoprotein E knockout mice: a proteomics approach. FASEB J. 2005;19:1746–8.
20. Munday JS, Thompson KG, James KA. Dietary conjugated linoleic acids promote fatty streak formation in the C57BL/6 mouse atherosclerosis model. Br J Nutr. 1999;81:251–5.[Medline]
21. Moloney F, Yeow T-P, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr. 2004;80:887–95.
22. Sarria AJ, Surra JC, Acín S, Carnicer R, Navarro MA, Arbonés-Mainar JM, Guillén N, Martínez-Gracia MV, Arnal C, Osada J. Understanding the role of dietary components on atherosclerosis using genetic engineered mouse models. Front Biosci. 2006;11:955–67.[Medline]
23. Roche HM, Noone E, Sewter C, Mc Bennett S, Savage D, Gibney MJ, O'Rahilly S, Vidal-Puig AJ. Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha. Diabetes. 2002;51:2037–44.
24. Acín S, Navarro MA, Carnicer R, Arbonés JM, Guzmán MA, Arnal C, Beltrán G, Uceda M, Maeda N, Osada J. Dietary cholesterol suppresses the ability of olive oil to delay the development of atherosclerotic lesions in apolipoprotein E knockout mice. Atherosclerosis. 2005;182:17–28.[Medline]
25. Navarro MA, Carpintero R, Acin S, Arbonés-Mainar JM, Calleja L, Carnicer R, Surra JC, Guzman-Garcia MA, Gonzalez-Ramon N, et al. Immune-regulation of the apolipoprotein A-I/C-III/A-IV gene cluster in experimental inflammation. Cytokine. 2005;31:52–63.[Medline]
26. Calleja L, Paris MA, Paul A, Vilella E, Joven J, Jimenez A, Beltran G, Uceda M, Maeda N, Osada J. Low-cholesterol and high-fat diets reduce atherosclerotic lesion development in apoE-knockout mice. Arterioscler Thromb Vasc Biol. 1999;19:2368–75.
27. Navarro MA, Acin S, Carnicer R, Guzman-Garcia MA, Arbones-Mainar JM, Surra JC, Cebrian JA, Arnal C, Isabel B, et al. Response of apoA-IV in pigs to long-term increased dietary oil intake and to the degree of unsaturation of the fatty acids. Br J Nutr. 2004;92:763–9.[Medline]
28. Calleja L, Trallero MC, Carrizosa C, Mendez MT, Palacios-Alaiz E, Osada J. Effects of dietary fat amount and saturation on the regulation of hepatic mRNA and plasma apolipoprotein A-I in rats. Atherosclerosis. 2000;152:69–78.[Medline]
29. Castellani LW, Navab M, Van Lenten BJ, Hedrick CC, Hama SY, Goto AM, Fogelman AM, Lusis AJ. Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles. J Clin Invest. 1997;100:464–74.[Medline]
30. Escola-Gil JC, Julve J, Marzal-Casacuberta A, Ordonez-Llanos J, Gonzalez-Sastre F, Blanco-Vaca F. Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. J Lipid Res. 2000;41:1328–38.
31. Warden CH, Hedrick CC, Qiao JH, Castellani LW, Lusis AJ. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science. 1993;261:469–72.
32. Brousseau ME, Hoeg JM. Transgenic rabbits as models for atherosclerosis research. J Lipid Res. 1999;40:365–75.
33. Kritchevsky D, Tepper SA, Wright S, Czarnecki SK, Wilson TA, Nicolosi RJ. Conjugated linoleic acid isomer effects in atherosclerosis: growth and regression of lesions. Lipids. 2004;39:611–6.[Medline]
34. Fruchart JC, Ailhaud G, Bard JM. Heterogeneity of high density lipoprotein particles. Circulation. 1993;87:III22–7.[Medline]
35. Marzal-Casacuberta A, Blanco-Vaca F, Ishida BY, Julve-Gil J, Shen J, Calvet-Marquez S, Gonzalez-Sastre F, Chan L. Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II. J Biol Chem. 1996;271:6720–8.
36. Weng W, Breslow JL. Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc Natl Acad Sci U S A. 1996;93:14788–94.
37. Wang CS, McConathy WJ, Kloer HU, Alaupovic P. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. J Clin Invest. 1985;75:384–90.[Medline]
38. Nguyen SD, Sok DE. Beneficial effect of oleoylated lipids on paraoxonase 1: protection against oxidative inactivation and stabilization. Biochem J. 2003;375:275–85.[Medline]
39. Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rubin EM. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001;294:169–73.
40. Baroukh N, Ostos MA, Vergnes L, Recalde D, Staels B, Fruchart J, Ochoa A, Castro G, Zakin MM. Expression of human apolipoprotein A-I/C-III/A-IV gene cluster in mice reduces atherogenesis in response to a high fat-high cholesterol diet. FEBS Lett. 2001;502:16–20.[Medline]
41. Baroukh N, Bauge E, Akiyama J, Chang J, Afzal V, Fruchart JC, Rubin EM, Fruchart-Najib J, Pennacchio LA. Analysis of apolipoprotein A5, C3, and plasma triglyceride concentrations in genetically engineered mice. Arterioscler Thromb Vasc Biol. 2004;24:1297–302.
42. Clement L, Poirier H, Niot I, Bocher V, Guerre-Millo M, Krief S, Staels B, Besnard P. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res. 2002;43:1400–9.
43. Tsuboyama-Kasaoka N, Takahashi M, Tanemura K, Kim HJ, Tange T, Okuyama H, Kasai M, Ikemoto S, Ezaki O. Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes. 2000;49:1534–42.[Abstract]
44. Belury MA, Kempa-Steczko A. Conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids. 1997;32:199–204.[Medline]
45. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005;111:1448–54.
46. Castellani LW, Gargalovic P, Febbraio M, Charugundla S, Jien ML, Lusis AJ. Mechanisms mediating insulin resistance in transgenic mice overexpressing mouse apolipoprotein A-II. J Lipid Res. 2004;45:2377–87.
47. Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, Leesnitzer LA, Belury MA. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res. 1999;40:1426–33.
48. Francis GA, Fayard E, Picard F, Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol. 2003;65:261–311.[Medline]
49. Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, Dong HH. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004;114:1493–503.[Medline]
50. Naiki T, Nagaki M, Shidoji Y, Kojima H, Imose M, Kato T, Ohishi N, Yagi K, Moriwaki H. Analysis of gene expression profile induced by hepatocyte nuclear factor 4alpha in hepatoma cells using an oligonucleotide microarray. J Biol Chem. 2002;277:14011–9.
51. Kelley DS, Bartolini GL, Warren JM, Simon VA, Mackey BE, Erickson KL. Contrasting effects of t10,c12- and c9,t11-conjugated linoleic acid isomers on the fatty acid profiles of mouse liver lipids. Lipids. 2004;39:135–41.[Medline]
52. Takahashi Y, Kushiro M, Shinohara K, Ide T. Activity and mRNA levels of enzymes involved in hepatic fatty acid synthesis and oxidation in mice fed conjugated linoleic acid. Biochim Biophys Acta. 2003;1631:265–73.[Medline]
53. Degrace P, Demizieux L, Gresti J, Chardigny J-M, Sébédio J-L, Clouet P. Hepatic steatosis is not due to impaired fatty acid oxidation capacities in C57BL/6J mice fed the conjugated trans-10,cis-12-isomer of linoleic acid. J Nutr. 2004;134:861–7.
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