客員教授 佐伯 武頼

2008/04/01
学位
医学博士 徳島大学
専門分野
生化学、病態生化学、人類遺伝学
職  歴
1965年 3月 徳島大学医学部医学科卒業
1966年 7月 医籍登録(番号192281号)
1970年 3月 徳島大学大学院医学研究科(酵素化学)単位取得退学
1970年 7月 徳島大学助手(医学部酵素研究施設酵素化学)
1972年 6月 西ドイツフライブルグ大学に海外出張(フライブルグ大学助手に採用、1974年3月まで)
1974年 4月 東海大学講師(医学部生化学講座)
1976年 4月 同上 助教授(医学部生化学講座)
1980年 12月 鹿児島大学教授(医学部生化学第1講座)
1999年 2月 鹿児島大学医学部長(2001年1月まで)
2003年 4月 鹿児島大学大学院医歯学総合研究科教授(分子病態生化学)
2006年 4月 徳島文理大学健康科学研究所教授(人間生活学部食物栄養学科)(2011年3月まで)
学  会
日本先天代謝異常学会理事、日本疾患モデル学会幹事、日本生化学会評議員、
日本肝臓学会会員、日本臨床化学学会会員、日本病態栄養学会会員

研究の概要
代謝異常疾患の病因と病態を解析し、治療法および発症予防法を開発することを目指しています。

特に窒素代謝異常に重点をおき、代謝異常疾患の病因を明らかにし、病態・発症機構を明らかにして、治療法を開発する、という研究を行っています。これまでに、尿素合成系の酵素欠損症については、臨床医・臨床研究者から、尿素サイクル酵素欠損症の確定診断を依頼され、すでに遺伝子診断を含め1000例以上の症例の確定診断を行ってきました。その中から、特にargininosuccinate synthetase (ASS)の欠損に起因するシトルリン血症とornithine carbamoyltransferase (OCT)欠損症については数多く解析し、それぞれの酵素異常の特徴を明らかにしました。また、シトルリン血症についてはASS遺伝子の変異解析を行い、その結果を踏まえ、遺伝子診断を行ってきました。

さらに、それらの臨床症例解析の結果、シトルリン血症を示すASS欠損症の中に新たな病態を見出し、II型シトルリン血症と名づけ(現在はCTLN2と略号でよばれ、上記のASS遺伝子異常に基づく疾患はCTLN1とよばれます)、その解析を進め、病因遺伝子SLC25A13を見出しました。さらに、その遺伝子産物をシトリンと名づけました。シトリンはその後の解析によって、ミトコンドリア膜に局在するaspartate/glutamate carrier (AGC) であることを明らかにしました。CTLN2は元来成人に見出される失見当識、行動異常、昏睡などから死に至る疾患ですが、SLC25A13変異を明らかにした結果、新生児期の病態を見いだし、NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency)と名づけました。その結果、シトリン欠損症という新しい疾患概念を打ち立てることが出来ました。

これらの高アンモニア血症を呈する疾患の病因に基づく治療法を開発するために、モデル動物が必要です。そこで、シトリン欠損症のモデルマウスを開発しました。現在、このマウスが本当にモデル動物として使えるものかどうかの検討を行っています。次には病因に基づく新しい治療法を検索しています。特に食事や栄養の面からの治療法を開発することが大切と考えています。

さらに、カルニチン欠損JVS (juvenile visceral steatosis)マウスやOCT欠損マウスを用いて、それらの病態解析、病態発症機構を解析し、治療法・治療効果の判定などを行っています。特にカルニチン欠損JVSマウスは、脂肪肝、高アンモニア血症、心肥大などだけでなく、絶食によって自発行動減少や食欲低下などをも発症することを見いだし、その発症機構を研究しています。

このような遺伝病の治療法の開発から出発し、今後はもっと一般的な、患者さんの多い生活習慣病の解析と新しい治療法の開発に取り掛かりたいと考えています。

主要論文・著書
1) Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R, Terazono H, Crackower MA, Kondo I, Tsui LC, Scherer SW, Saheki T.: The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet. 1999;22(2):159-63.

2) Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrustegui J, Palmieri F.: Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2000;20(18):5060-9.

3) Sinasac DS, Moriyama M, Jalil MA, Begum L, Li MX, Iijima M, Horiuchi M, Robinson BH, Kobayashi K, Saheki T, Tsui LC.: Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol. 2004;24(2):527-36.

4) Moriyama M, Li MX, Kobayashi K, Sinasac DS, Kannan Y, Iijima M, Horiuchi M, Tsui LC, Tanaka M, Nakamura Y, Saheki T.: Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice.
J Hepatol. 2006;44(5):930-8.

5) Saheki T, Iijima M, Li MX, Kobayashi K, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowaki T, Sinasac DS, Tsui LC, Tsuji M, Okano A, Kobayashi T. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J Biol Chem. 2007;282(34):25041-52.

最近5年間の論文・総論
1) Ko JM, Kim GH, Kim JH, Kim JY, Choi JH, Ushikai M, Saheki T, Kobayashi K, Yoo HW.: Six cases of citrin deficiency in Korea. Int J Mol Med. 2007;20(6):809-15.

2) Saheki T, Iijima M, Li MX, Kobayashi K, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowaki T, Sinasac DS, Tsui LC, Tsuji M, Okano A, Kobayashi T.: Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency. J Biol Chem. 2007;282(34):25041-52.

3) Satrústegui J, Contreras L, Ramos M, Marmol P, del Arco A, Saheki T, Pardo B.: Role of aralar, the mitochondrial transporter of aspartate-glutamate, in brain N-acetylaspartate formation and Ca(2+) signaling in neuronal mitochondria. J Neurosci Res. 2007;85(15):3359-66.

4) Dimmock D, Kobayashi K, Iijima M, Tabata A, Wong LJ, Saheki T, Lee B, Scaglia F.: Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics. 2007r;119(3):e773-7.

5) Ohura T, Kobayashi K, Tazawa Y, Abukawa D, Sakamoto O, Tsuchiya S, Saheki T.: Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis. 2007;30(2):139-44.

6) Contreras L, Gomez-Puertas P, Iijima M, Kobayashi K, Saheki T, Satrústegui J.: Ca2+ Activation kinetics of the two aspartate-glutamate mitochondrial carriers, aralar and citrin: role in the heart malate-aspartate NADH shuttle. J Biol Chem. 2007;282(10):7098-106.

7) Tazawa K, Shimojima Y, Okano T, Yazaki M, Takei Y, Shimojo H, Kobayashi K, Saheki T, Ikeda S.: An autopsy case with adult onset type II citrullinemia showing myelopathy. J Neurol Sci. 2007;253(1-2):77-80.

8) Lu YB, Peng F, Li MX, Kobayashi K, Saheki T.: Progresses and perspectives in the study on citrin deficiency. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006;23(6):655-8. Chinese.

9) Tokuhara D, Iijima M, Tamamori A, Ohura T, Takaya J, Maisawa S, Kobayashi K, Saheki T, Yamano T, Okano Y.: Novel diagnostic approach to citrin deficiency: analysis of citrin protein in lymphocytes. Mol Genet Metab. 2007;90(1):30-6.

10) Li MX, Yoshida G, Horiuchi M, Kobayashi K, Saheki T.: Prolonged effect of single carnitine administration on fasted carnitine-deficient JVS mice regarding their locomotor activity and energy expenditure. Biochim Biophys Acta. 2006;1761(10):1191-9.

11) Terada R, Yamamoto K, Kobayashi K, Sakaguchi K, Iwasaki Y, Saheki T, Shiratori Y.: Adult-onset type II citrullinemia associated with idopathic hypertriglyceridemia as a preceding feature. J Gastroenterol Hepatol. 2006;21(10):1634-5.

12) Lee NC, Chien YH, Kobayashi K, Saheki T, Chen HL, Chiu PC, Ni YH, Chang MH, Hwu WL. Time course of acylcarnitine elevation in neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis. 2006;29(4):551-5.

13) Song YZ, Hao H, Ushikai M, Liu GS, Xiao X, Saheki T, Kobayashi K, Wang ZN.: A difficult and complicated case study: neonatal intrahepatic cholestasis caused by citrin deficiency. Zhongguo Dang Dai Er Ke Za Zhi. 2006;8(2):125-8.

14) Yoshida G, Li MX, Horiuchi M, Nakagawa S, Sakata M, Kuchiiwa S, Kuchiiwa T, Jalil MA, Begum L, Lu YB, Iijima M, Hanada T, Nakazato M, Huang ZL, Eguchi N, Kobayashi K, Saheki T.: Fasting-induced reduction in locomotor activity and reduced response of orexin neurons in carnitine-deficient mice. Neurosci Res. 2006;55(1):78-86.

15) Moriyama M, Li MX, Kobayashi K, Sinasac DS, Kannan Y, Iijima M, Horiuchi M, Tsui LC, Tanaka M, Nakamura Y, Saheki T.: Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice. J Hepatol. 2006;44(5):930-8.

16) Abdul Jalil M, Horiuchi M, Wakamatsu M, Li MX, Begum L, Suzuki K, Kobayashi K, Oka T, Saheki T.: Attenuation of Cardiac Hypertrophy in Carnitine-Deficient Juvenile Visceral Steatosis (JVS) Mice Achieved by Lowering Dietary Lipid. J Biochem (Tokyo). 2006;139(2):263-70.

17) Takahashi H, Kagawa T, Kobayashi K, Hirabayashi H, Yui M, Begum L, Mine T, Takagi S, Saheki T, Shinohara Y.: A case of adult-onset type II citrullinemia--deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit. 2006;12(2):CS13-5.

18) Ezgu FS, Tumer L, Dalgic B, Hasanoglu A, Kobayashi K, Saheki T.: Cirrhosis in an infant heterozygous for classical citrullinaemia. Acta Paediatr. 2005;94(12):1849-51.

19) Takaya J, Kobayashi K, Ohashi A, Ushikai M, Tabata A, Fujimoto S, Yamato F, Saheki T, Kobayashi Y.: Variant clinical courses of 2 patients with neonatal intrahepatic cholestasis who have a novel mutation of SLC25A13. Metabolism. 2005;54(12):1615-9.

20) Takagi H, Hagiwara S, Hashizume H, Kanda D, Sato K, Sohara N, Kakizaki S, Takahashi H, Mori M, Kaneko H, Ohwada S, Ushikai M, Kobayashi K, Saheki T.: Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis. J Hepatol. 2006;44(1):236-9.

21) Pardo B, Contreras L, Serrano A, Ramos M, Kobayashi K, Iijima M, Saheki T, Satrustegui J.: Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria. J Biol Chem. 2006;281(2):1039-47.

22) Saheki T, Kobayashi K, Iijima M, Moriyama M, Yazaki M, Takei YI, Ikeda SI.: Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatol Res. 2005;33(2):181-4.

23) Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, Lei L, Kawabe K, Taura S, Yang Y, Liu TT, Chiang SH, Hsiao KJ, Lau YL, Tsui LC, Lee DH, Saheki T.: Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet. 2005;50(7):338-46.

24) Jalil MA, Begum L, Contreras L, Pardo B, Iijima M, Li MX, Ramos M, Marmol P, Horiuchi M, Shimotsu K, Nakagawa S, Okubo A, Sameshima M, Isashiki Y, Del Arco A, Kobayashi K, Satrustegui J, Saheki T.: Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J Biol Chem. 2005;280(35):31333-9.

25) Yazaki M, Takei Y, Kobayashi K, Saheki T, Ikeda S.: Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Intern Med. 2005;44(3):188-95.

26) Tazawa Y, Abukawa D, Sakamoto O, Nagata I, Murakami J, Iizuka T, Okamoto M, Kimura A, Kurosawa T, Iinuma K, Kobayashi K, Saheki T, Ohura T.: A possible mechanism of neonatal intrahepatic cholestasis caused by citrin deficiency. Hepatol Res. 2005 Mar;31(3):168-171.

27) Hachisu M, Oda Y, Goto M, Kobayashi K, Saheki T, Ohura T, Noma S, Kitanaka S.: Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr. 2005;164(2):109-10.

28) Ito S, Kurasawa G, Yamamoto K, Furuta I, Ishihara F, Kobayashi K, Saheki T, Matsuura T, Yamauchi M, Kakinoki H.: A pregnant patient with fulminant hepatic failure was found to carry a novel missense mutation in the argininosuccinate synthetase gene. J Gastroenterol. 2004;39(11):1115-7.

29) Tazawa Y, Kobayashi K, Abukawa D, Nagata I, Maisawa S, Sumazaki R, Iizuka T, Hosoda Y, Okamoto M, Murakami J, Kaji S, Tabata A, Lu YB, Sakamoto O, Matsui A, Kanzaki S, Takada G, Saheki T, Iinuma K, Ohura T.: Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab. 2004;83(3):213-9.

30) Ikeda S, Kawa S, Takei Y, Yamamoto K, Shimojo H, Tabata K, Kobayashi K, Saheki T.: Chronic pancreatitis associated with adult-onset type II citrullinemia: clinical and pathologic findings. Ann Intern Med. 2004 Oct 5;141(7):W109-10.

31) Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, Takei H, Shigematsu Y, Hata I, Ozaki H, Tokuhara D, Nishimura Y, Yorifuji T, Igarashi N, Ohura T, Shimizu T, Inui K, Sakai N, Abukawa D, Miyakawa T, Matsumori M, Ban K, Kaneko H, Yamano T.: Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. 2004;56(4):608-14.

32) Potter MA, Zeesman S, Brennan B, Kobayashi K, Gao HZ, Tabata A, Saheki T, Whelan DT.: Pregnancy in a healthy woman with untreated citrullinemia. Am J Med Genet A. 2004;129(1):77-82.

33) Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y.: Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab. 2004;81 Suppl 1:S20-6.

34) Yazaki M, Hashikura Y, Takei Y, Ikegami T, Miyagawa S, Yamamoto K, Tokuda T, Kobayashi K, Saheki T, Ikeda S.: Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia. Liver Transpl. 2004;10(4):550-4.

35) Nishimura Y, Tajima G, Dwi Bahagia A, Sakamoto A, Ono H, Sakura N, Naito K, Hamakawa M, Yoshii C, Kubota M, Kobayashi K, Saheki T.: Differential diagnosis of neonatal mild hypergalactosaemia detected by mass screening: clinical significance of portal vein imaging. J Inherit Metab Dis. 2004;27(1):11-8.

36) Sinasac DS, Moriyama M, Jalil MA, Begum L, Li MX, Iijima M, Horiuchi M, Robinson BH, Kobayashi K, Saheki T, Tsui LC.: Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol. 2004;24(2):527-36.

37) Kobayashi K, Bang Lu Y, Xian Li M, Nishi I, Hsiao KJ, Choeh K, Yang Y, Hwu WL, Reichardt JK, Palmieri F, Okano Y, Saheki T.: Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations. Mol Genet Metab. 2003;80(3):356-9.

38) Hagiwara N, Sekijima Y, Takei Y, Ikeda S, Kawasaki S, Kobayashi K, Saheki T.: Hepatocellular carcinoma in a case of adult-onset type II citrullinemia. Intern Med. 2003;42(10):978-82.

39) Gao HZ, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Trefz FK, Skladal D, Mandel H, Seidel J, Kodama S, Shirane S, Ichida T, Makino S, Yoshino M, Kang JH, Mizuguchi M, Barshop BA, Fuchinoue S, Seneca S, Zeesman S, Knerr I, Rodes M, Wasant P, Yoshida I, De Meirleir L, Abdul Jalil M, Begum L, Horiuchi M, Katunuma N, Nakagawa S, Saheki T.: Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003;22(1):24-34.

40) Imamura Y, Kobayashi K, Shibatou T, Aburada S, Tahara K, Kubozono O, Saheki T.: Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res. 2003;26(1):68-72.

41) Ramos M, del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K, Yasuda T, Bogonez E, Bovolenta P, Saheki T, Satrustegui J.: Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res. 2003;143(1):33-46.

42) Ohura T, Kobayashi K, Abukawa D, Tazawa Y, Aikawa J, Sakamoto O, Saheki T, Iinuma K.: A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Eur J Pediatr. 2003;162(5):317-22.

43) Ruitenbeek W, Kobayashi K, Iijima M, Smeitink JA, Engelke UF, De Abreu RA, Kwast HT, Saheki T, Boelen CA, De Jong JG, Wevers RA.: Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase. Ann Clin Biochem. 2003;40(Pt 1):102-7.
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