臺灣博碩士論文加值系統

血清澱粉狀蛋白（serum amyloid A, SAA）為載脂蛋白的一種，在發炎反應時可大量表現，並且具有置換另一個位於高密度脂蛋白（high density lipoprotein, HDL）上的載脂蛋白A1的能力。當以富含二十二碳六烯酸（docosahexaenoic acid, DHA）之飼料餵飼豬隻時，可提高肝臟中SAA的表現。本試驗之目的在於釐清豬隻SAA對於代謝相關基因的調控。首先為了得知SAA所調控的基因為何，以人類HepG2細胞株培養於含有2 μM人類SAA重組蛋白之培養液中72小時，抽取RNA進行微陣列基因晶片分析。試驗發現，SAA會降低許多脂肪酸代謝基因的表現，包括轉錄因子過氧化小體增生活化受體α（peroxisome proliferator-activated receptor α, PPARα, P<0.01）、肝細胞核因子4α（hepatocyte nuclear factor 4α, HNF4α, P<0.01），而固醇調節因子結合蛋白1c（sterol regulatory element binding protein 1c, SREBP1c）則未受影響。脂肪酸合成酶（Fatty acid synthase）、acyl-CoA oxidase及liver type fatty acid binding protein（L-FABP）則會受SAA的抑制。因此推測人類SAA可以藉由抑制過氧小體增生活化受體α的表現而達到調控脂質代謝的目的。

為了瞭解豬隻SAA所扮演的角色，本研究首先證明SAA大量的表現於豬隻的肝臟組織，所以從肝臟cDNA中選殖該基因進行後續研究。序列分析之結果指出豬SAA蛋白質N端具有一段分泌的訊息序列，顯示SAA為一具有外泌能力的蛋白質。而將此基因架接於pQE-31表現載體後，成功產製保有SAA活性的重組蛋白，豬隻的SAA可刺激豬脂肪前身細胞介白素-6（interleukin 6）的表現（P<0.05），此結果符合在人類脂肪前身細胞所觀察到的現象。當以2 μM豬SAA重組蛋白處理脂肪細胞後可抑制PPARα及PPARγ的表現（分別降低40％及60％），SAA亦會增加發炎反應激素基因表現（如介白素-6）及細胞內甘油的釋出，顯示細胞的脂質分解作用增加，同時也發現SAA處理時保護脂肪堆積的蛋白質perilipin的表現受到抑制，而且由於perilipin的抑制會增加內泌素敏感解脂酶（hormone sensitive lipase, HSL）活性，所以推測SAA可藉由降低perilipin的表現而增加脂質分解作用。由於PPARγ的標的基因，adipocyte FABP與脂蛋白解脂酶（lipoprotein lipase）也受到抑制，推測細胞內的脂肪酸攝入會隨之下降。

綜言之， SAA於HepG2細胞株中具有調控脂質代謝基因表現的能力。在豬隻的試驗中，由DHA刺激產生的SAA可能參與抑制轉錄因子PPARs及其下游基因的表現，因此我們推測SAA在DHA調控體內脂質代謝中扮演了重要的角色。

Serum amyloid A protein (SAA) is an apolipoprotein, whose concentration increases during acute inflammation, and can replace apolipoprotein A1 (apoA1), the major apolipoprotein of HDL. Porcine SAA mRNA is increased by dietary docosahexaenoic acid (DHA) treatment. The purpose of this study was to investigate the role of SAA protein in regulating gene expression related to lipid metabolism in pigs. In the first experiment, human cell line, HepG2, was treated with 2 μM SAA for 3 days. Microarray technology was utilized to explore candidate genes regulated by the SAA treatment. The SAA down-regulated several genes involved in fatty acid metabolism, including transcription factors peroxisome proliferator-activated receptor α (PPARα, P<0.01) and hepatocyte nuclear factor 4α (HNF4α, P<0.01). Fatty acid synthase, acyl-CoA oxidase, and liver type fatty acid binding protein were also repressed by the SAA treatment, suggesting that SAA may exert its effects by suppressing the expression of PPARα to modify the expression of aforementioned genes. In order to further extend understandings about the role of SAA in pigs, porcine liver was first demonstrated abundant SAA gene expression. In the next study, porcine SAA gene was cloned from the liver showing that there is a signal peptide sequence, a strong evidence for porcine SAA as a secretory protein. Construction of the recombinant protein expression system in pQE-31 vector to express porcine SAA in E. coli. (M15 strain) was conducted. The addition of porcine SAA recombinant protein (pSAA) in porcine preadipocyte culture stimulated interleukin-6 (IL-6) mRNA expression (P<0.05), indicating a similar biological function of porcine SAA as compared with that in human. Peroxisome proliferator-activated receptor α (PPARα) and PPARγ mRNA was decreased by 40% and 60%, respectively, in differentiated adipocytes when treated with 2 μM pSAA. In addition, the SAA treatment caused a dramatic increase of inflammatory cytokine gene expressions (e.g., IL-6), and glycerol release, indicating an increase of lipolysis. Because the expression of perilipin, a lipid droplet-protective protein, was reduced by the SAA treatment, and the reduced perilipin would increase hormone sensitive lipase (HSL) activity, the increase of lipolysis by the SAA treatment may be mediated by decreasing perilipin.
In conclusion, the present study demonstrated that SAA can affect the expression of lipid metabolism related transcription factors in HepG2 cells. In pigs, the DHA-induced SAA gene expression decrease PPAR expression and therefore, down-regulates the target genes expression. Accordingly, SAA may play a critical role in mediating the function of dietary DHA on lipid metabolism.

目錄 --------------------------------------------------------------------------- Ⅰ
中文摘要 --------------------------------------------------------------------------- Ⅱ
英文摘要 --------------------------------------------------------------------------- Ⅳ
圖次 --------------------------------------------------------------------------- Ⅵ
表次 --------------------------------------------------------------------------- Ⅷ
文獻檢討 --------------------------------------------------------------------------- 1
材料與方法 --------------------------------------------------------------------------- 17
結果與討論 --------------------------------------------------------------------------- 57
結論 --------------------------------------------------------------------------- 74
參考文獻 --------------------------------------------------------------------------- 77

Abe-Dohmae, S., K. H. Kato, Y. Kumon, W. Hu, H. Ishigami, N. Iwamoto, M. Okazaki, C. A. Wu, M. Tsujita, K. Ueda, and S. Yokoyama. 2006. Serum amyloid a generates high density lipoprotein with cellular lipid in an ABCA1- or ABCA7-dependent manner. J Lipid Res 47: 1542-1550.
Banka, C. L., T. Yuan, M. C. de Beer, M. Kindy, L. K. Curtiss, and F. C. de Beer. 1995. Serum amyloid a （SAA）: Influence on hdl-mediated cellular cholesterol efflux. J Lipid Res 36: 1058-1065.
Baranova, I. N., T. G. Vishnyakova, A. V. Bocharov, R. Kurlander, Z. Chen, M. L. Kimelman, A. T. Remaley, G. Csako, F. Thomas, T. L. Eggerman, and A. P. Patterson. 2005. Serum amyloid a binding to CLA-1 （CD36 and limpii analogous-1） mediates serum amyloid a protein-induced activation of erk1/2 and p38 mitogen-activated protein kinases. J Biol Chem 280: 8031-8040.
Berk, P. D., and D. D. Stump. 1999. Mechanisms of cellular uptake of long chain free fatty acids. Mol Cell Biochem 192: 17-31.
Brown, M. S., and J. L. Goldstein. 1999. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A 96: 11041-11048.
Cai, L., M. C. de Beer, F. C. de Beer, and D. R. van der Westhuyzen. 2005. Serum amyloid a is a ligand for scavenger receptor class b type 1 and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem 280: 2954-2961.
Cao, G., C. K. Garcia, K. L. Wyne, R. A. Schultz, K. L. Parker, and H. H. Hobbs. 1997. Structure and localization of the human gene encoding SR-B1/CLA-1. Evidence for transcriptional control by steroidogenic factor 1. J Biol Chem 272: 33068-33076.
Carmen, G. Y., and S. M. Victor. 2006. Signalling mechanisms regulating lipolysis. Cell Signal 18: 401-408.
Chang, W. J., C. H. Chen, W. T. K. Cheng, and S. T. Ding. 2007. The effects of dietary docosahexaenoic acid enrichment on the expression of porcine genes. Asian-Aust. J. Anim. Sci. 20: 768-774.
Chen, C. H., E. C. Lin, W. T. Cheng, H. S. Sun, H. J. Mersmann, and S. T. Ding. 2006. Abundantly expressed genes in pig adipose tissue: An expressed sequence tag approach. J Anim Sci 84: 2673-2683.
Chomczynski, P., and N. Sacchi. 1987. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156-159.
Costet, P., Y. Luo, N. Wang, and A. R. Tall. 2000. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240-28245.
Curtiss, L. K., D. T. Valenta, N. J. Hime, and K. A. Rye. 2006. What is so special about apolipoprotein A1 in reverse cholesterol transport? Arterioscler Thromb Vasc Biol 26: 12-19.
Dalen, K. T., K. Schoonjans, S. M. Ulven, M. S. Weedon-Fekjaer, T. G. Bentzen, H. Koutnikova, J. Auwerx, and H. I. Nebb. 2004. Adipose tissue expression of the lipid droplet-associating proteins s3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-γ. Diabetes 53: 1243-1252.
Desvergne, B., L. Michalik, and W. Wahli. 2006. Transcriptional regulation of metabolism. Physiol Rev 86: 465-514.
Ding, S. T., A. Lapillonne, W. C. Heird, and H. J. Mersmann. 2003. Dietary fat has minimal effects on fatty acid metabolism transcript concentrations in pigs. J Anim Sci 81: 423-431.
Ding, S. T., A. P. Schinckel, T. E. Weber, and H. J. Mersmann. 2000. Expression of porcine transcription factors and genes related to fatty acid metabolism in different tissues and genetic populations. J Anim Sci 78: 2127-2134.
Duplus, E., M. Glorian, and C. Forest. 2000. Fatty acid regulation of gene transcription. J Biol Chem 275: 30749-30752.
Edwards, P. A., D. Tabor, H. R. Kast, and A. Venkateswaran. 2000. Regulation of gene expression by SREBP and SCAP. Biochim Biophys Acta 1529: 103-113.
Escriva, H., F. Delaunay, and V. Laudet. 2000. Ligand binding and nuclear receptor evolution. Bioessays 22: 717-727.
Fasshauer, M., J. Klein, S. Kralisch, M. Klier, U. Lossner, M. Bluher, and R. Paschke. 2004. Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. J Endocrinol 183: 561-567.
Festuccia, W. T., M. Laplante, M. Berthiaume, Y. Gelinas, and Y. Deshaies. 2006. PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control. Diabetologia 49: 2427-2436.
Fielding, C. J., and P. E. Fielding. 1995. Molecular physiology of reverse cholesterol transport. J Lipid Res 36: 211-228.
Field, F. J., E. Born, S. Murthy, and S. N. Mathur. 2002. Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CACO-2 cells: Effect on fatty acid synthesis and triacylglycerol transport. Biochem J 368: 855-864.
Fujiwara, Y., M. Yokoyama, R. Sawada, Y. Seyama, M. Ishii, S. Tsutsumi, H. Aburatani, S. Hanaka, H. Itakura, and A. Matsumoto. 2003. Analysis of the comprehensive effects of polyunsaturated fatty acid on mRNA expression using a gene chip. J Nutr Sci Vitaminol （Tokyo） 49: 125-132.
Galli, E., M. Picardo, L. Chini, S. Passi, V. Moschese, O. Terminali, F. Paone, G. Fraioli, and P. Rossi. 1994. Analysis of polyunsaturated fatty acids in newborn sera: A screening tool for atopic disease? Br J Dermatol 130: 752-756.
Hagihara, K., T. Nishikawa, T. Isobe, J. Song, Y. Sugamata, and K. Yoshizaki. 2004. IL-6 plays a critical role in the synergistic induction of human serum amyloid A （SAA） gene when stimulated with proinflammatory cytokines as analyzed with an saa isoform real-time quantitative RT-PCR assay system. Biochem Biophys Res Commun 314: 363-369.
Hajri, T., R. Elliott-Bryant, J. D. Sipe, J. S. Liang, K. C. Hayes, and E. S. Cathcart. 1998. The acute phase response in apolipoprotein A-1 knockout mice: Apolipoprotein serum amyloid A and lipid distribution in plasma high density lipoproteins. Biochim Biophys Acta 1394: 209-218.
Han, C. Y., T. Chiba, J. S. Campbell, N. Fausto, M. Chaisson, G. Orasanu, J. Plutzky, and A. Chait. 2006. Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-1 and paraoxonase-1 by inflammation in murine hepatocytes. Arterioscler Thromb Vasc Biol 26: 1806-1813.
He, R., L. W. Shepard, J. Chen, Z. K. Pan, and R. D. Ye. 2006. Serum amyloid a is an endogenous ligand that differentially induces IL-12 and IL-23. J Immunol 177: 4072-4079.
Horton, J. D. 2002. Sterol regulatory element-binding proteins: Transcriptional activators of lipid synthesis. Biochem Soc Trans 30: 1091-1095.
Hsu, J. M., and S. T. Ding. 2003. Effect of polyunsaturated fatty acids on the expression of transcription factor adipocyte determination and differentiation-dependent factor 1 and of lipogenic and fatty acid oxidation enzymes in porcine differentiating adipocytes. Br J Nutr 90: 507-513.
Hsu, J. M., P. H. Wang, B. H. Liu, and S. T. Ding. 2004. The effect of dietary docosahexaenoic acid on the expression of porcine lipid metabolism-related genes. J Anim Sci 82: 683-689.
Jernas, M., J. Palming, K. Sjoholm, E. Jennische, P. A. Svensson, B. G. Gabrielsson, M. Levin, A. Sjogren, M. Rudemo, T. C. Lystig, B. Carlsson, L. M. Carlsson, and M. Lonn. 2006. Separation of human adipocytes by size: Hypertrophic fat cells display distinct gene expression. Faseb J 20: 1540-1542.
Ji, Y., B. Jian, N. Wang, Y. Sun, M. L. Moya, M. C. Phillips, G. H. Rothblat, J. B. Swaney, and A. R. Tall. 1997. Scavenger receptor B1 promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem 272: 20982-20985.
Kerner, J., and C. Hoppel. 2000. Fatty acid import into mitochondria. Biochim Biophys Acta 1486: 1-17.
Kim, H. J., M. Takahashi, and O. Ezaki. 1999. Fish oil feeding decreases mature sterol regulatory element-binding protein 1 （SREBP-1） by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs. J Biol Chem 274: 25892-25898.
Kim, J. Y., K. Tillison, J. H. Lee, D. A. Rearick, and C. M. Smas. 2006. The adipose tissue triglyceride lipase ATGl/PNPLA2 is downregulated by insulin and TNFα in 3T3-L1 adipocytes and is a target for transactivation by PPARγ. Am J Physiol Endocrinol Metab 291: E115-127.
Knight, B. L., A. Hebbachi, D. Hauton, A. M. Brown, D. Wiggins, D. D. Patel, and G. F. Gibbons. 2005. A role for PPARα in the control of srebp activity and lipid synthesis in the liver. Biochem J 389: 413-421.
Kreutz, F. H. 1962. Enzymatic glycerin determination. Klin Wochenschr 40: 362-363.
Kumon, Y., T. Suehiro, D. J. Faulkes, T. Hosakawa, Y. Ikeda, P. Woo, J. D. Sipe, and K. Hashimoto. 2002. Transcriptional regulation of serum amyloid A1 gene expression in human aortic smooth muscle cells involves CCAAT/enhancer binding proteins （C/EBP） and is distinct from HepG2 cells. Scand J Immunol 56: 504-511.
Landschulz, K. T., R. K. Pathak, A. Rigotti, M. Krieger, and H. H. Hobbs. 1996. Regulation of scavenger receptor, class b, type 1, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J Clin Invest 98: 984-995.
Langelier, B., J. P. Furet, M. H. Perruchot, and J. M. Alessandri. 2003. Docosahexaenoic acid membrane content and mRNA expression of acyl-CoA oxidase and of peroxisome proliferator-activated receptor-δ are modulated in y79 retinoblastoma cells differently by low and high doses of alpha-linolenic acid. J Neurosci Res 74: 134-141.
Langin, D., and P. Arner. 2006. Importance of TNFα and neutral lipases in human adipose tissue lipolysis. Trends Endocrinol Metab 17: 314-320.
Liang, J. S., and J. D. Sipe. 1995. Recombinant human serum amyloid A （apoSAAp） binds cholesterol and modulates cholesterol flux. J Lipid Res 36: 37-46.
Liang, J. S., B. M. Schreiber, M. Salmona, G. Phillip, W. A. Gonnerman, F. C. de Beer, and J. D. Sipe. 1996. Amino terminal region of acute phase, but not constitutive, serum amyloid A （apoSAA） specifically binds and transports cholesterol into aortic smooth muscle and HepG2 cells. J Lipid Res 37: 2109-2116.
Lindhorst, E., D. Young, W. Bagshaw, M. Hyland, and R. Kisilevsky. 1997. Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse. Biochim Biophys Acta 1339: 143-154.
Liu, B. H., Y. C. Wong, F. C. Kuo, W. M. Cheng, T. F. Shen, and S. T. Ding. 2005. The effects of docosahexaenoic acid oil and soybean oil on the expression of lipid metabolism related mRNA in pigs. Asian-Aust. J. Anim. Sci. 18: 1451-1456.
Marcus, S. L., K. S. Miyata, B. Zhang, S. Subramani, R. A. Rachubinski, and J. P. Capone. 1993. Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression. Proc Natl Acad Sci U S A 90: 5723-5727.
McGarry, J. D., G. P. Mannaerts, and D. W. Foster. 1977. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 60: 265-270.
Michalopoulos, G. K., and M. DeFrances. 2005. Liver regeneration. Adv Biochem Eng Biotechnol 93: 101-134.
Mikawa, A., H. Suzuki, K. Suzuki, D. Toki, H. Uenishi, T. Awata, and N. Hamasima. 2004. Characterization of 298 ESTs from porcine back fat tissue and their assignment to the ssrh radiation hybrid map. Mamm Genome 15: 315-322.
Minihane, A. M. 2005. Fatty acid, gene expression, and coronary heart disease. Nutrigenomic: 181-199.
Narayanan, B. A., N. K. Narayanan, and B. S. Reddy. 2001. Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int J Oncol 19: 1255-1262.
Ntambi, J. M., and K. Young-Cheul. 2000. Adipocyte differentiation and gene expression. J Nutr 130: 3122S-3126S.
O''Hea, E. K., and G. A. Leveille. 1969. Significance of adipose tissue and liver as sites of fatty acid synthesis in the pig and the efficiency of utilization of various substrates for lipogenesis. J Nutr 99: 338-344.
Osborne, T. F. 2000. Sterol regulatory element-binding proteins （SREBPs）: Key regulators of nutritional homeostasis and insulin action. J Biol Chem 275: 32379-32382.
Parra, M. D., P. Fuentes, F. Tecles, S. Martinez-Subiela, J. S. Martinez, A. Munoz, and J. J. Ceron. 2006. Porcine acute phase protein concentrations in different diseases in field conditions. J Vet Med B Infect Dis Vet Public Health 53: 488-493.
Path, G., S. R. Bornstein, M. Gurniak, G. P. Chrousos, W. A. Scherbaum, and H. Hauner. 2001. Human breast adipocytes express interleukin-6 （IL-6） and its receptor system: Increased IL-6 production by β-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 86: 2281-2288.
Patton, J. S., H. M. Shepard, H. Wilking, G. Lewis, B. B. Aggarwal, T. E. Eessalu, L. A. Gavin, and C. Grunfeld. 1986. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc Natl Acad Sci U S A 83: 8313-8317.
Pawar, A., and D. B. Jump. 2003. Unsaturated fatty acid regulation of peroxisome proliferator-activated receptorα activity in rat primary hepatocytes. J Biol Chem 278: 35931-35939.
Poirier, H., I. Niot, M. C. Monnot, O. Braissant, C. Meunier-Durmort, P. Costet, T. Pineau, W. Wahli, T. M. Willson, and P. Besnard. 2001. Differential involvement of peroxisome-proliferator-activated receptors α and δ in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine. Biochem J 355: 481-488.
Poitou, C., N. Viguerie, R. Cancello, R. De Matteis, S. Cinti, V. Stich, C. Coussieu, E. Gauthier, M. Courtine, J. D. Zucker, G. S. Barsh, W. Saris, P. Bruneval, A. Basdevant, D. Langin, and K. Clement. 2005. Serum amyloid A: Production by human white adipocyte and regulation by obesity and nutrition. Diabetologia 48: 519-528.
Puppione, D. L., J. P. Whitelegge, L. M. Yam, and V. N. Schumaker. 2005. Mass spectral analysis of pig （Sus. scrofa） apo HDL: Identification of pig apoA-2, a dimeric apolipoprotein. Comp Biochem Physiol B Biochem Mol Biol 141: 89-94.
Ren, B., A. P. Thelen, J. M. Peters, F. J. Gonzalez, and D. B. Jump. 1997. Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and s14 gene expression does not require peroxisome proliferator-activated receptor α. J Biol Chem 272: 26827-26832.
Rojas, C. V., J. I. Martinez, I. Flores, D. R. Hoffman, and R. Uauy. 2003. Gene expression analysis in human fetal retinal explants treated with docosahexaenoic acid. Invest Ophthalmol Vis Sci 44: 3170-3177.
Rothblat, G. H., M. de la Llera-Moya, V. Atger, G. Kellner-Weibel, D. L. Williams, and M. C. Phillips. 1999. Cell cholesterol efflux: Integration of old and new observations provides new insights. J Lipid Res 40: 781-796.
Ryden, M., E. Arvidsson, L. Blomqvist, L. Perbeck, A. Dicker, and P. Arner. 2004. Targets for TNFα-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 318: 168-175.
Sandberg, M. B., M. Bloksgaard, D. Duran-Sandoval, C. Duval, B. Staels, and S. Mandrup. 2005. The gene encoding acyl-CoA-binding protein is subject to metabolic regulation by both sterol regulatory element-binding protein and peroxisome proliferator-activated receptor α in hepatocytes. J Biol Chem 280: 5258-5266.
Schmittgen, T. D., B. A. Zakrajsek, A. G. Mills, V. Gorn, M. J. Singer, and M. W. Reed. 2000. Quantitative reverse transcription-polymerase chain reaction to study mRNA decay: Comparison of endpoint and real-time methods. Anal Biochem 285: 194-204.
Schreiber, B. M., M. Veverbrants, R. E. Fine, J. K. Blusztajn, M. Salmona, A. Patel, and J. D. Sipe. 1999. Apolipoprotein serum amyloid A down-regulates smooth-muscle cell lipid biosynthesis. Biochem J 344 Pt 1: 7-13.
Shimano, H., N. Yahagi, M. Amemiya-Kudo, A. H. Hasty, J. Osuga, Y. Tamura, F. Shionoiri, Y. Iizuka, K. Ohashi, K. Harada, T. Gotoda, S. Ishibashi, and N. Yamada. 1999. Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 274: 35832-35839.
Sjoholm, K., J. Palming, L. E. Olofsson, A. Gummesson, P. A. Svensson, T. C. Lystig, E. Jennische, J. Brandberg, J. S. Torgerson, B. Carlsson, and L. M. Carlsson. 2005. A microarray search for genes predominantly expressed in human omental adipocytes: Adipose tissue as a major production site of serum amyloid A. J Clin Endocrinol Metab 90: 2233-2239.
Staels, B., and J. Auwerx. 1998. Regulation of apo A-1 gene expression by fibrates. Atherosclerosis 137 Suppl: S19-23.
Steffensen, K. R., and J. A. Gustafsson. 2004. Putative metabolic effects of the liver X receptor （LXR）. Diabetes 53 Suppl 1: S36-42.
Stonik, J. A., A. T. Remaley, S. J. Demosky, E. B. Neufeld, A. Bocharov, and H. B. Brewer. 2004. Serum amyloid A promotes ABCA1-dependent and ABCA1-independent lipid efflux from cells. Biochem Biophys Res Commun 321: 936-941.
Stulnig, T. M. 2003. Immunomodulation by polyunsaturated fatty acids: Mechanisms and effects. Int Arch Allergy Immunol 132: 310-321.
Sumida, M., K. Sekiya, H. Okuda, Y. Tanaka, and T. Shiosaka. 1990. Inhibitory effect of tumor necrosis factor on gene expression of hormone sensitive lipase in 3T3-L1 adipocytes. J Biochem （Tokyo） 107: 1-2.
Suresh, Y., and U. N. Das. 2003. Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus. Effect of omega-3 fatty acids. Nutrition 19: 213-228.
Takahashi, A., K. Motomura, T. Kato, T. Yoshikawa, Y. Nakagawa, N. Yahagi, H. Sone, H. Suzuki, H. Toyoshima, N. Yamada, and H. Shimano. 2005. Transgenic mice overexpressing nuclear SREBP-1c in pancreatic β-cells. Diabetes 54: 492-499.
Tecles, F., P. Fuentes, S. Martinez Subiela M. D. Parra, A. Munoz, and J. J. Ceron. 2007. Analytical validation of commercially available methods for acute phase proteins quantification in pigs. Res Vet Sci. 83: 133-139
Thorn, C. F., Z. Y. Lu, and A. S. Whitehead. 2003. Tissue-specific regulation of the human acute-phase serum amyloid A genes, SAA1 and SAA2, by glucocorticoids in hepatic and epithelial cells. Eur J Immunol 33: 2630-2639.
Tobin, K. A., S. M. Ulven, G. U. Schuster, H. H. Steineger, S. M. Andresen, J. A. Gustafsson, and H. I. Nebb. 2002. Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem 277: 10691-10697.
Trayhurn, P., and I. S. Wood. 2004. Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92: 347-355.
Uhlar, C. M., and A. S. Whitehead. 1999. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265: 501-523.
Upragarin, N., W. J. Landman, W. Gaastra, and E. Gruys. 2005. Extrahepatic production of acute phase serum amyloid A. Histol Histopathol 20: 1295-1307.
van der Westhuyzen, D. R., L. Cai, M. C. de Beer, and F. C. de Beer. 2005. Serum amyloid A promotes cholesterol efflux mediated by scavenger receptor B1. J Biol Chem 280: 35890-35895.
Vandesompele, J., K. De Preter, F. Pattyn, B. Poppe, N. Van Roy, A. De Paepe, and F. Speleman. 2002. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: RESEARCH0034.
van Hall, G., A. Steensberg, M. Sacchetti, C. Fischer, C. Keller, P. Schjerling, N. Hiscock, K. Moller, B. Saltin, M. A. Febbraio, and B. K Pedersen. 2003. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88: 3005-3010.
Wallenius, V., K. Wallenius, B. Ahren, M. Rudling, H. Carlsten, S. L. Dickson, C. Ohlsson, and J. O. Jansson. 2002. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8: 75-79.
Wolfrum, C., C. M. Borrmann, T. Borchers, and F. Spener. 2001. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α - and γ-mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus. Proc Natl Acad Sci U S A 98: 2323-2328.
Xu, J., M. Teran-Garcia, J. H. Park, M. T. Nakamura, and S. D. Clarke. 2001. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J Biol Chem 276: 9800-9807.
Yahagi, N., H. Shimano, A. H. Hasty, M. Amemiya-Kudo, H. Okazaki, Y. Tamura, Y. Iizuka, F. Shionoiri, K. Ohashi, J. Osuga, K. Harada, T. Gotoda, R. Nagai, S. Ishibashi, and N. Yamada. 1999. A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J Biol Chem 274: 35840-35844.
Yang, R. Z., M. J. Lee, H. Hu, T. I. Pollin, A. S. Ryan, B. J. Nicklas, S. Snitker, R. B. Horenstein, K. Hull, N. H. Goldberg, A. P. Goldberg, A. R. Shuldiner, S. K. Fried, and D. W. Gong. 2006. Acute-phase serum amyloid A: An inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 3: e287.
Yoshikawa, T., H. Shimano, N. Yahagi, T. Ide, M. Amemiya-Kudo, T. Matsuzaka, M. Nakakuki, S. Tomita, H. Okazaki, Y. Tamura, Y. Iizuka, K. Ohashi, A. Takahashi, H. Sone, J. Osuga Ji, T. Gotoda, S. Ishibashi, and N. Yamada. 2002. Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor （LXR） binding to lxr response elements. J Biol Chem 277: 1705-1711.
Young, S. G., and C. J. Fielding. 1999. The abcs of cholesterol efflux. Nat Genet 22: 316-318.
Yu, Y. H., B. H. Liu, H. J. Mersmann, and S. T. Ding. 2006. Porcine peroxisome proliferator-activated receptor γ induces transdifferentiation of myocytes into adipocytes. J Anim Sci 84: 2655-2665.
Zelcer, N., and P. Tontonoz. 2006. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116: 607-614.