系統
系統:  AD/1 (Albumin deficient rat: inbred strain)), ACI-alb (Analbuminemic congenic strain),NAR (Nagase analbuminemia rat) 
キーワード:  無アルブミン血症、高脂血症、アルブミン遺伝子、スプライ シング異常 
由来:  1977年に(財)実験動物中央研究所の服部らはJcl:SDラット にラードを負荷し、血清コレステロール上昇群と非上昇群を分離した。(財)佐々木 研究所の長瀬らはこれをF4で譲り受け、リポタンパク質や脂質代謝などの研究中に偶然無アルブミン血症個体を発見し、この子孫をもとにしてミュータント系のNAR (Nagase Analbuminemic Rat)を確立した(1979年)。朱宮らはNARをもとに近交系(1987)およびコンジェニッ ク系(1986)を育成した。 
表現型・病態:  血清蛋白電気泳動によりアルブミンバンドの欠損によって無アルブミン血症を確認できる。正常ラットに比べて繁殖性に差はなく1年以上にわたって繁殖可能である。血清中の総タンパク質量に差はなくアルブミンの欠損をグロブ リンで代償している。軽度貧血、易溶血性傾向を示し、タンパク質代謝異常による BUN値の上昇傾向が認められる。肝臓は有意に重いが肝機能は正常である。加齢とともに著しい高脂血症を呈し、コレステロールの代謝回転が速い。 
病因(原因遺伝子):  ラットのアルブミン遺伝子(Alb)は第14番染色体末端部に座位し、NARではHI イントロンにおける5'端に近い部分で7塩基対の欠損があり、スプライシングの過程でmRNAのHエキソンが抜け肝臓におけるアルブミン生合成が進行しないためにアルブミン欠損症となる。 
臨床への応用、有用性:  ヒトの無アルブミン血症は1954年にBennhold らが最初の報告をして以来30例 以上の症例が報告されている。これらの中には異なる部 位でのポイントミューテーション、挿入、フレームシフトなどの例が報告され、ヒトの無アルブミン血症には遺伝子構造上の変異が認められる。無アルブミンラットは生体内でのアルブミン合成過程におけるスプライシング機構の研究に有用であり、分子治療実験にも利用されている。またアルブミンは全血清タンパク質の50~60%を占め 、構造的に遊離脂肪酸、ビリルビン、金属イオン、ホルモン、薬物などの特異的な結合部位をもつためキャリヤータンパク質としてのアルブミン機能の解析や高脂血症治療薬のスクリーニング、臓器移植など多彩なアルブミン関与機構の研究に利用されている。 
維持機関:  日本エスエルシー株式会社 :AD/1 (NAR)を維持・供給 〒431-1103 静岡県浜松市湖東町3371-8 TEL 053-486-3178 FAX 053-486-3156 アーク・リソース株式会社:ACI-albの受精卵保存 〒861-5271 熊本県熊本市中原町383-2 TEL 096-329-0880 FAX 096-329-0882 
文献:  Shalaby, F. and Shafritz, D. A. Exon skipping during splicing of albumin mRNA precursors in Nagase analbuminemic rats. PNAS 87: 2652-2656, 1990. Nishikawa, Y., Sakai, H., Inagaki, M., Fukuda, I., Ogawa, K. and Nagase, S. Genotypic differentiation of intrahepatically transplanted hyperplastic nodule cells of analbuminemic and normal rat origin by polymerase chain reaction. Jpn. J. Cancer Res. 81: 711-714, 1990. Tanaka, H., Matsuhisa, A., Nagamori, S., Shimizu, K., Niiya, M., Ohno, T. and Nagase, S. Characteristics and significance of albumin-positive hepatocytes in analbuminemic rats. Eur. J. Cell Biol. 53: 267-274, 1990. Davies, R. W., Staprans, I., Hutchison, F. N. and Kaysen, G. A. Proteinuria, not altered albumin metabolism, affects hyperlipidemia in the nephrotic rat. J. Clin. Invest. 86: 500-505, 1990. Kaneko, T., Shima, H., Esumi, H., Ochiai, M., Nagase, S., Sugimura, T. and Nagao, M. Marked increases of two kinds of two-exon-skipped albumin mRNAs with aging and their further increase by treatment with 3'-metyl-4-dimetylaminoazobebzene in Nagase analbuminemic rats. PNAS 88: 2707-2711, 1991. 0chiai, M., Ogawa, K., Wakabayashi, K., Sugimura, T., Nagase, S., Esumi, H. and Nagao, M. Induction of intestinal adenocarcinomas by 2-amino-1-metyl-6-phenylimidazo-[4,5-b]pyridine in Nagase analbuminemic rats. Jpn. J. Cacer Res. 82: 363-366, 1991. Wu, G. Y., Wilson, J. M., Shalaby, F., Grossman, M., Shafritz, D. A. and Wu, C. H. Receptor-mediated gene delivery in vivo: Partial correction of genetic analbuminemia in Nagase rats. J. Biol. Chem. 266: 14338-14342, 1991. Joles, J. A., Willekes-Koolschijin, N., Van Tol, A., Geelhoed-Mieras, M. M., Danse, L. H. J. C., Van Garderen, E., Kortlandt, W. Erkelens, D. W. and Koomans, H. A. Hyperlipoproteinemia in one-year-old analbuminemic rats. Atherosclerosis 88: 35-47, 1991.  Van Tol, A., Jansen, E. H. J. M., Koomans, H. A. and Joles, J. A. Hyperlipoproteinemia in Nagase analbuminemic rats: Effects of pravastatin on plasma (apo)lipoproteins and lecithin: cholesterol acyltransferase activity. J. Lipid Res. 32: 1719-1728, 1991. Yaschuk, D. M., Sanker,J. M., Zhou, J., Wilson, N. and Keeler, R. Abnormal renal response to twenty-four-hour dehydration and fasting in Nagase analbuminemic rats. Lab. Anim. Sci. 41: 577-580, 1991. Usuki, S., Maekawa, A., Kang, H., Shumiya, S. and Nagase, S. High susceptibility of analbuminemic rats to neurogenic tumor induction by transplacental administration of N-ethyl-N-nitorosourea. Jpn. J. Cancer Res. 83: 146-152, 1992. Sun, X., Jones, H., Joles, J. A., Van Tol, A. and Kaysen, G. A. Apolipoprotein gene expression in analbuminemic rats and in rats with Heymann nephritis. Am. J. Physiol. 262: F755-761, 1992. Yamamoto, Y., Wakabayashi, K., Niki, E. and Nagao, M. Comparison of plasma levels of lipid hydroperoxides and antioxidants in hyperlipidemic Nagase analbuminemic rats, Sprague-Dawley rats, and humans. BBRC 189: 518-523, 1992. Joles, J. A., Willekes-Koolschijn, N., Koomans, H., Van Tol, A., Geelhoed-Mieras, T., Crommelin, D., Van Bloois, L., Krajnc-Fraanken, M., Choen, L., Griffioen, M. and Erkelens, W. Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats. Lab. Anim. 26: 269-280, 1992. Fujihara, C. K. Limongi, D. M. Z. P., DeOliveira, H. C. F. and Zatz, R. Absence of focal glomerulosclerosis in aging analbuminemic rats. Am. J. Physiol. 262: R947-954, 1992. Dragan, Y. P., Laufer, C., Koleske, A. J., Drinkwater, N. and Pitot, H. C. Quantitative comparison of initiation and mutation phenotypes in hepatocytes of the analbuminemic rat. Jpn. J. Cancer Res. 84: 175-183, 1993. Renkin, E. M., Tucker, V. L., Wiig, H., Kaysen, G., Sibley, L., Decarlo, M., Simanonok, K. and Wong, M. Blood-tissue transport of exogenous albumin and immunoglobulin G in genetically analbuminemic rats. J. Appl. Physiol. 74: 559-566, 1993. Joles, J. A. Feingold, K. R., Van Tol., A., Cohen, L. H., Sun, X., Jones, H., Davies, R. W. and Kaysen, G. A. Extrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic rat. Am. J. Physiol. 265: F70-76, 1993. 0hta, T., Ogawa, K. and Nagase, S. Increase on albumin mRNA by repeated intrahepatic transplantation of F344 rat hepatocytes into the liver of congenic analbuminemic rats. BBRC 194: 601-609, 1993. 0hta, T., Ogawa, K. and Nagase, S. Elevation of serum albumin by intrahepatic transplantation of albumin-producing cells does not correct quantitative abnormalities of non-albumin proteins in analbuminemic rats. BBRC 197: 1103-1110, 1993. Catanozzi, S., Rocha, J. C., Nakandakare, E. R., Oliveira, H. C. F. and Quintao, E. C. R. Nagase analbuminemic rat have faster plasma triacyl-glycerol and VLDL synthesis rates. BBA 1212: 103-108, 1994. Sun, X. and Kaysen, G. A. Albulmin and transferrin synthesis are increased in H4 ce l ls by serum from analbuminemic or nephrotic rats. Kidney Int. 45: 1381-1387, 1994. Joles, J. A., Willekes-Koolschijn, N., Scheek, L. M., Koomans, H. A., Rabelink, T. J. and Van Tol, A. Lipoprotein phospholipid composition and LCAT activity in nephrotic and analbuminemic rats. Kidney Int. 46: 97-104, 1994. Vargas, E. J., Shoho, A. R. and Linder, M. A. Copper transport in the Nagase analbuminemic rat. Am. J. Physiol. 267: G259-269, 1994. Joles, J. A., Van Goor, H., Braam, B., Willekes-Koolschijn, N., Jaansen, E. H. J. M., VanTol, A. and Koomans, H. A. Proteinuria, lipoproteins and renal apolipoprotein deposits in uninephrectomized female analbuminemic rats. Kidney Int. 47: 442-453, 1995. Joles, J. A., Bijleveld, C., Van Tol, A., Geelen, M. J. H. and Koomans, H. A. Plasma triglyceride levels are higher in nephrotic than in analbuminemic rats despite a similar increase in hepatic triglyceride secretion. Kidney Int. 47: 566-572, 1995. Joles, J. A., Bijleveld, C., Van Tol, A., Geelen, M. J. H. and Koomans, H. A. 0variectomy decreases plasma triglyceride levels in analbuminemic rats by lowering hepatic triglyceride secretion. Atherosclerosis 117: 51-59, 1995. Joles, J. A., Van Goor, H., Van der Horst, M. L. C., Van Tol, A., Elema, J. D. and Koomans, H. A. High lipid levels in very 1ow density lipoprotein and intermediate density lipoprotein may cause proteinuria and glomerulosclerosis in aging female analbuminemic rats. Lab. Invest. 73: 912-921, 1995. Fabrega, A. J., Fasbender, A. J., Struble, S and Zabner, J. Cationic lipid-mediated transfer of the hIL-l0 gene prolongs survival of allogeneic hepatocytes in Nagase analbuminemic rats. Transplantaion 62: 1866-1871, 1996. Takeda, A., Kawai, M. and 0kada, S. Zinc distribution in the brain of Nagase analbuminemic rat and enlargement of the ventricular system. Brain Res. 769: 193-195, 1997. Kambe, A., Uchuda, K., Takase, H., Nomura, Y. and Adachi, Y. Bile acid metabolism in analbuminemic rats. Lipids 33: 93-100, 1998. Stevenson, F. T., Greene, S. and Kaysen, G. A. Serum α2-macroglobulin and α1-inhibitor 3 concentrations are increased in hypoalbuminemia by post-transcriptional mechanism. Kidney Int. 53: 67-75, 1998. Joles, J. A., Van Goor, H. and Koomans, H. A. Estrogen induses glomerulosclerosis in analbuminemic rats. Kidny Int. 53: 862-868, 1998. Hitomi, Y., Sugiyama, K., and Esumi, H. Suppression of the 5' splice site mutation in the Nagase analbuminemic rat with mutated U1snRNA. BBRC 251: 11-16.1998. Oren, R., Dabeva, M. D., Petkov, P. M., Hurston, E., Laconi, E. and Shafritz, D. A. Restration of serum albumin levels in Nagase analbuminemic rats by hepatocyte transplantation. Hepatology 29(1): 75-81, 1999. Ikebukuro, H., Inagaki, M., Mito, M., Kasai, S., Ogawa, K. and Nozawa, M. Prolonged function of hepatocytes transplanted into the spleens of Nagase analbuminemic rats. Eur. Surg. Res. 31(1): 39-47, 1999. Kishihara, K., Ohta, M., Hashizume, M., Tomikawa, M., Kawanaka, H., Tanoue, K., Higashi, H. and Sugimachi, K. Systemic effects of ethanolamine oleation in analbuminemic rats. Hepatogastroenterogy. 46(25): 376-380, 1999. Inaba, M., Morii, H., Katsumata, T., Goto, H., Ishimura, E., Kawagishi, T., Kamao, M., Okano, T. and Nishizawa, Y. Hyperparathyroidism is augmented by ovariectomyin Nagase analbuminemic rats. J. Nutr. 130(6): 1543-1547, 2000. Shearer, G. C., Joles, J. A., Jones, H., Walzem, R. L. and Kaysen, G. A. Estrogen effets on triglyceride metabolism in analbuminemic rats. Kidney Int. 57(6): 2268-2274, 2000. Sierra, E., Maganto, P., Codesal, J., Mula, N., Cubero, J., Arza, E., Castillo-Olivares, J. L. and Arahuetes, R. M. Liver gene expression and increase in albumin synthsis by fetal hepatocytes transplanted into analbuminemic rats. Life Sci. 67(20): 2417-2432, 2000. Takada, K., Kawamura, T., Inai, M., Masuda, S., Oka, T., Yoshikawa, Y., Shibata, N., Yoshikawa, H., Wada, H. and Hitomi, S. Pharmacokinetics of cisplatin in analbuminemic rats. Biopharm. Drug Dispos. 20(9): 421-428, 1999. David, P., Alexander, E., Chenard-Neu, M. P., Audet, M., Wolf, P., Jaeck,D., Azimzadeh, A. and Richert, L. Engraftment and function of freshly isolated and cryopreserved Sprague-Dawley rat hepatocytes after intrasplenic transplantation in analbuminemic rat. Transplant Proc. 32(8): 2796-2797, 2000. David, P., Alexander, E., Audet, M., Chenard-Neu, M. P., Wolf, P., Jaeck, D., Azimzadeh, A. and Richert, L. Engraftment and albumin production of intrasplenically transplanted rat hepatocytes (Sprague-Dawley), freshly isolated versus cryopreserved, into Nagase analbuminemic rat (NAR). Cell Transplant. 10(1): 67-80, 2001. Kim, E. J. and Lee, M. G. Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant Nagase analbuminemic rats. Biopharm. Drug Dispos. 24: 27-35, 2003. Kim, E. J., Suh, O.K. and Lee, M. G. Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats. Life Sci. 72: 1231-1245, 2003. 
執筆者記録:  朱宮正剛  2004年7月1日 
close window to return to the search page.