解酮障碍SCOT基因突变与临床研究
|
摘要
背景酮体是能量从肝脏向肝外组织转移的主要载体[1],主要在肝脏生成。体内酮体浓度增加时即发生酮症酸中毒。琥珀酰辅酶A转硫酶(SCOT)是酮体能量代谢的关键酶,位于多个组织的线粒体内,其作用是将琥珀酰辅酶A的辅酶A基团转移至乙酰乙酸从而催化乙酰乙酰辅酶A的形成,这一步骤是酮体利用的第一步,随后乙酰乙酰辅酶A进一步断裂成两分子的乙酰辅酶A进入三羧酸循环。研究表明:SCOT催化乙酰乙酰辅酶A生成的具体机制是与辅酶A的巯基生成硫酯并以非共价键的形式连接辅酶A的ADP基团。硫酯形成的部位位于SCOT肽链第344位谷氨酸的羧基上。SCOT缺乏导致发作性的酮症酸中毒,为常染色体隐形遗传,大多数情况下作为儿童酮症酸中毒鉴别诊断的一部分。与大多数有机酸血症不同的是,除乙酰乙酸和3-羟基丁酸等酮体增加外,这类病人的血和(或)尿液中无其他诊断性的代谢产物出现。自1972年J.T.Tildon等报道的第一例SCOT缺陷病人至今,只发现18例先证者[1-12]]和10种突变类型[3,5,6,8-12]。
目的探讨解酮障碍SCOT基因突变类型以及解酮障碍患者基因型和临床表型之间的关系。
方法提取3例临床高度SCOT基因缺陷所致解酮障碍患儿以及50例正常对照儿童外周血总RNA,进行RT-PCR反应,扩增整个SCOT cDNA编码区片段并克隆测序,对RNA检测异常的患儿进行DNA检测;观察基因突变患儿的临床表现。
结果3例患者中,1例发现12外显子的跳跃现象,DNA水平检测发现12外显子第48位碱基发生替代(c1147G>A)。mRNA前体二级结构分析显示12外显子的这种替代确实改变了正常序列的mRNA前体二级结构,ESE分析提示碱基替代位点所在的这段嘌呤富集区作为ESE的可能性并不大。其余2例未发现突变。SCOT基因12外显子跳跃的患儿表现为感染诱发的反复发作的严重酮症酸中毒,经积极抢救症状能缓解,发作间歇期患儿同正常儿童,生长发育正常。
结论SCOT基因12外显子48位碱基的替代是否通过改变mRNA前体的二级结构而导致12外显子跳跃仍有待进一步的证实。该突变在国内外未见报道。对SCOT基因12外显子跳跃的患儿应避免感染,发作时应进行积极救治。
Background Ketone body are major vectors of energy transfer from liver to extrahepatic tissues[1] which are mainly produced in liver. Ketoscidosis occurs commonly under the condition of a marked increase in ketone body concentration. Succinyl CoA: 3-oxoacid CoA transferase(SCOT) is the key enzyme of ketone body utilization, existing in the mitochondrial matrix of multiple organs. SCOT catalyzes the reversible transfer of a CoA moiety from succinyl CoA to the ketone body acetoacetate, the first step of ketone- body utilization. Then, acetoacetyl CoA cleavage to two acetyl CoA molecules which are capable of entering the tricarboxylic acid cycle. Elegant studies revealed that, the special mechanism of SCOT catalyzing the formation of acetoacetyl CoA is generating the thioester with coenzyme A and binding the ADP groups of coenzyme A in the form of non–covalent bond. The formation of thioester occurs in on the glutamate residue344 of SCOT peptide chain. Hereditary deficiency of SCOT is an autosomal recessive inborn error and is part of the differential diagnosis of childhood ketoacidosis , a frequently occurring condition. In contrast with most organic acidemias, no diagnostic metabolites are observed in blood and urine samples from SCOT-deficient patients although the ketone bodies acetoacetate and 3-hydroxybutyrate are elevated. Since the first description of SCOT deficiency, only 18 [1-12]]affedted probands and 10 mutations have been reported[3,5,6,8-12].
Objective To explore the mutations types of Chinese SCOT-deficient patient and the relationship between the genotype and phenotype.
Method Total RNA was extracted from peripheral blood of clinical highly suspected children and 50 health children as control, the whole coding sequence of SCOT cDNA was amplified by RT-PCR followed by T-Clone and sequencing.DNA was teseted if RNA was tested abnormal; observed the clinical manifestions of the child who had SCOT gene mutations.
Result One of there patients was found with skipping of exon 12, detection in DNA level showed a single-base substitution(c1147G>A)in exon 12. The pre-mRNA secondary structure analysis revealed a change of pre-mRNA secondary structure after substitution while the ESE analysis told us that the purine-rich region was unlikely acting as ESEs. The other two were found no mutations. The child who had 12 exon skip of SCOT gene mainly manifested as recurrent infection induced severe ketoacidosis, but the symptoms could released by active salvage, and the patient could be as normal as other children during the intermittent episodes.
Conclusion Whether the substitution of exon 12(c1147G>A)resulted in the skipping of 12 by disrupting the pre-RNA secondary structure needs to be further confirmed. Thjs mutation had not been reported before. Infection should be avoided if the child has this kind of mution, and treatment should be active.
目的探讨解酮障碍SCOT基因突变类型以及解酮障碍患者基因型和临床表型之间的关系。
方法提取3例临床高度SCOT基因缺陷所致解酮障碍患儿以及50例正常对照儿童外周血总RNA,进行RT-PCR反应,扩增整个SCOT cDNA编码区片段并克隆测序,对RNA检测异常的患儿进行DNA检测;观察基因突变患儿的临床表现。
结果3例患者中,1例发现12外显子的跳跃现象,DNA水平检测发现12外显子第48位碱基发生替代(c1147G>A)。mRNA前体二级结构分析显示12外显子的这种替代确实改变了正常序列的mRNA前体二级结构,ESE分析提示碱基替代位点所在的这段嘌呤富集区作为ESE的可能性并不大。其余2例未发现突变。SCOT基因12外显子跳跃的患儿表现为感染诱发的反复发作的严重酮症酸中毒,经积极抢救症状能缓解,发作间歇期患儿同正常儿童,生长发育正常。
结论SCOT基因12外显子48位碱基的替代是否通过改变mRNA前体的二级结构而导致12外显子跳跃仍有待进一步的证实。该突变在国内外未见报道。对SCOT基因12外显子跳跃的患儿应避免感染,发作时应进行积极救治。
Background Ketone body are major vectors of energy transfer from liver to extrahepatic tissues[1] which are mainly produced in liver. Ketoscidosis occurs commonly under the condition of a marked increase in ketone body concentration. Succinyl CoA: 3-oxoacid CoA transferase(SCOT) is the key enzyme of ketone body utilization, existing in the mitochondrial matrix of multiple organs. SCOT catalyzes the reversible transfer of a CoA moiety from succinyl CoA to the ketone body acetoacetate, the first step of ketone- body utilization. Then, acetoacetyl CoA cleavage to two acetyl CoA molecules which are capable of entering the tricarboxylic acid cycle. Elegant studies revealed that, the special mechanism of SCOT catalyzing the formation of acetoacetyl CoA is generating the thioester with coenzyme A and binding the ADP groups of coenzyme A in the form of non–covalent bond. The formation of thioester occurs in on the glutamate residue344 of SCOT peptide chain. Hereditary deficiency of SCOT is an autosomal recessive inborn error and is part of the differential diagnosis of childhood ketoacidosis , a frequently occurring condition. In contrast with most organic acidemias, no diagnostic metabolites are observed in blood and urine samples from SCOT-deficient patients although the ketone bodies acetoacetate and 3-hydroxybutyrate are elevated. Since the first description of SCOT deficiency, only 18 [1-12]]affedted probands and 10 mutations have been reported[3,5,6,8-12].
Objective To explore the mutations types of Chinese SCOT-deficient patient and the relationship between the genotype and phenotype.
Method Total RNA was extracted from peripheral blood of clinical highly suspected children and 50 health children as control, the whole coding sequence of SCOT cDNA was amplified by RT-PCR followed by T-Clone and sequencing.DNA was teseted if RNA was tested abnormal; observed the clinical manifestions of the child who had SCOT gene mutations.
Result One of there patients was found with skipping of exon 12, detection in DNA level showed a single-base substitution(c1147G>A)in exon 12. The pre-mRNA secondary structure analysis revealed a change of pre-mRNA secondary structure after substitution while the ESE analysis told us that the purine-rich region was unlikely acting as ESEs. The other two were found no mutations. The child who had 12 exon skip of SCOT gene mainly manifested as recurrent infection induced severe ketoacidosis, but the symptoms could released by active salvage, and the patient could be as normal as other children during the intermittent episodes.
Conclusion Whether the substitution of exon 12(c1147G>A)resulted in the skipping of 12 by disrupting the pre-RNA secondary structure needs to be further confirmed. Thjs mutation had not been reported before. Infection should be avoided if the child has this kind of mution, and treatment should be active.
引文
[1] G.A. Mitchell, T. Fukao, Inborn errors of ketone body catabolism[J].Metabolic and Molecular Bases of Inherited Disease.2001(102):2327–2356.
[2] J.T. Tildon, M. Cornblath, Succinyl-CoA:3-ketoacid CoA transferase deficiency: a cause for ketoacidosis in infancy[J].Clin. Invest. 1972(51):493–498.
[3] S. Kassovska-Bratinoba, T. Fukao, X.Q. Song, et al, Succinyl CoA:3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient[J]. Am. J. Hum. Genet.1996(59) :519– 528.
[4] X.Q. Song, T. Fukao, G.A. Mitchell, et al, Succinyl-CoA: 3-ketoacid coenzyme A transferase (SCOT): development of an antibody to human SCOT and diagnostic use in hereditary SCOT deficiency.[J]Biochim. Biophys.Acta 1997(1360): 151–156.
[5] X.Q. Song, T. Fukao, H. Watanabe, H. et al, Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings.[J]Hum. Mutat.1998(12):83–88.
[6] T. Fukao, G.A. Mitchell, X.Q. Song, H. Nakamura, et al, Succinyl-CoA: 3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations.[J]Genomics 2000(68):144–151.
[7] G.T.Berry, T. Fukao, G.A. Mitchell, et al, Neonatal hypoglycemia in severe succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency.[J]Inherit.Metab. Dis. 2000(24):587–595.
[8] N. Longo, T. Fukao, R. Singh, et al, Succinyl-CoA:3-keto acid transferase (SCOT) deficiency in a new patient homozygous for an R217X mutation.[J]Inherit. Metab. Dis. 2004(27):691–692.
[9] T. Fukao, H. Shintaku, R. Kusubae, et al, Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA transferase (SCOT) do not show permanent ketosis.[J]Pediatr. Res.2004(56):858–863.
[10]Toshiyuki Fukao, Satomi Sakurai, et al. A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency.[J]Mol Genet Metab.2006(89):280-282.
[11] Fukao T, Kursula P, et al.Identification and characterization of a temperature- sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(29):216-221.
[12] Keitaro Yamada,Toshiyuki Fukao, et. Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(90):291-297.
[13] Mitchell GA, Fukao T . Inborn errors of ketone body catabolism. In: Scriver CR,Beaudet AL, Sly WS, Valle D (eds) Metabolic and Molecular Bases of Inherited Disease, 8th Ed. McGraw-Hill, New York,2001 pp 2327–2356.
[14] Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.1992,330- 340.
[15] Balasse Eo, Fery F. Ketonee body production and disposal: effects of fasting, diabetes and exercise.[J]Diabetes Metab Rev 1989(5):247-270.
[16] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase.[J]Am. J. Physiol. Heart. Circ. Physiol. 2001(281):2289–2294.
[17] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA- transferase in rats after endotoxin administration,Proc. Natl. Acad. Sci. (USA)2001(98): 7146–7151.
[18] Wahle E and Keller W. The biochemistry of 3’-end cleavage and polyadenil- ation RNA precursors.[J]Annu. Rev. Biochem, 1992(61): 419-440.
[19] Sacha Kassovska-Bratinova, Toshiyuki Fukao, Xiang-Qian Song. Succinyl CoA:3-Oxoacid CoA Transferase (SCOT): Human cDNA Cloning, Human Chromosomal Mapping to 5pl 3, and Mutation Detection in a SCOT-Deficient Patient.[J]Am. J. Hum.Genet. 1996(59):519-528.
[20]Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.1992,330-340.
[21] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase.[J]Am. J. Physiol. Heart. Circ. Physiol. 2001(281):2289–2294.
[22] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA- transferase in rats after endotoxin administration,Proc. Natl. Acad. Sci. (USA) 2001 (98): 7146–7151.
[23] Spector Aa:Fatty acid binding to plasma albumin.[J]Lipid Res 1975(15):165-179.
[24]Ockner Rk, Kaikaus Rm, Bass Nm: Fatty acid bingding proteins: recent concepts of regulation and function. In: Coates P, Tanaka K eds. New development in fatty acid oxidation. New York: Wihey-Liss, Inc.1992,189-204.
[25]Stanley Ca: Plasma and mitochondrial membrane carnitine transport defedts. In: Coates P, Tanaka K, eds. New developments in fatty acid oxidation. New York: Wiley-Liss, Inc. 1992,289-300.
[26] Uchida Y, Izai K, Orii T. Hashimoto T: Novel fatty acid beta-oxidation enzymes in rat liver mitochondria.[J]Biol Chem 1992(267):1034-1041.
[27]Alessandra Kupper Cardozo, Linda De Meirleir, et al. Analysis of Exonic Mutations Leading to Exon Skipping in Patients with Pyruvate Dehydrogenase E1a Deficiency.[J]Pediatr. Res. 2000(48):748–752.
[28] Keitaro Yamada,Toshiyuki Fukao, et al. Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(90):291-297
[29]Sakazaki H, Hirayama K, Murakami S, et al. A new Japaneses case of succinyl- CoA: 3-ketoacid CoA-transferase deficiency.[J]Inher Metab Dis 1995(18):323-325.
[30]Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev 2003(17):419–437.
[31] Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single base pair substitutions in mRNA splice junctions of human genes: causes and consequences.[J]Hum Genet 1992(90):41–54.
[32]Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN.[J]Hum Mol Genet 2000(9):259–265.
[33]Blencowe, B. J. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases.[J]Trends Biochem Sci.2000(25):106–110.
[34] Clouet d’Orval BC, d’Aubenton Carafa YA, et al. RNA secondary structure repression of a muscle-specific exon in HeLa cell nuclear extracts.[J]Science1991 (252):1823–1828.
[35]Libri D, Piseri A, Fiszman MY .Tissue-specific splicing in vivo of the b-tropomyosin gene: dependence on an RNA secondary structure.[J]Science 1991(252): 1842–1845.
[36] Coleman TP, Roesser JR.RNA secondary structure: an important cis-element in rat calcitonin/CGRP pre-messenger RNA splicing.[J]Biochemistry1998(37):15941– 15950.
[37]Muro AF, Caputi M, Pariyarath R, et al.Regulation of fibronectin EDA exon alternative splicing: possible role of RNA secondary structure for enhancer display.[J]Mol Cell Biol 1999(19):2657–2671.
[38]Cartegni, L, Chew, S.L., and Krainer, A.R., Listening to silence and understanding nonsense exonic mutations that affect splicing.[J]Nat Rev Genet, 2000(3): 285-298.
[39]Alessandra Kupper Cardozo, Linda De Meirleir, et al. Analysis of Exonic Mutations Leading to Exon Skipping in Patients with Pyruvate Dehydrogenase E1a Deficiency.[J]Pediatr. Res. 2000(48):748–752.
[40]Maniatis, T. and Tasic, B, Alternative pre-mRNA splicing and proteome expansion in metazoans.[J]Nature. 2000(418): 236-243.
[41]Toshiyuki Fukao, Haruki Nakamura, Xiang-Qian Song, et al. Characteriztion of N93S, I312T, and A333P mission mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency.[J] Hum Muta.1998(12):245-254.
[1] G.A. Mitchell, T. Fukao, Inborn errors of ketone body metabolism, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle(Eds.), The Metabolic and Molecular Bases of Inherited Disease,McGraw-Hill, New York, 2001, pp. 2327–2356.
[2] Robingson Am, Willimson Dh, Physiological roles of ketone bodies as substrates and signals in mammalian tissues[J]. Physiol Rev 60:143-87,1980.
[3] Mcgarry Jd, Foster Dw: Rrgulation of hepatic fatty acid oxidation and ketone body production[J]. Ann Rev Biochem 49:395-420,1980.
[4] Mcgarry Jd, Woeltje Kf, Kuwajima M, et al. Regulation of ketogenesis snd the renaissance of carnitine palmitoyltransferanse[J].Diabetes Metab Rev5:271-284,1989.
[5] Balasse Eo, Fery F. Ketonee body production and disposal: effects of fasting, diabetes and exercise[J].Diabetes Metab Rev 5:247-270,1989.
[6]Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.330-340,1992
[7] Nosadini R, Avogaro A, Dofia A, et al. Ketone body metabolism: a physiological and clinical overview[J].Diabetes Metab Rev 5:299-319,1989.
[8] Guthrie Jp, Jordan F. Amine-catalyzed decarboxylation of acetoacetic acid. The rate constant for decarboxylation of beta-immino acid.[J]. Am Chem Soc 94: 9136-9141, 1972
[9] Seymour KJ, Bluml S, Sutherling J, et al. Identi￠cation of cerebral acetone by H-MRS in patients with epilepsy controlled by ketogenic diet[J]. MAGMA 8:33-42,1999.
[10] Likhodii SS, Serbanescu I, Cortez MA,et al.Anti-convulsant properties of acetone, a brain ketone elevated by the ketogenic diet[J].Ann Neurol54: 219-226,2003.
[11]Newsholme Ea, Leech Ar. Biochemistry for the medical sciences. New York: John Wiley &Sons, 1983.
[12]Jungermann K, Katz N. Functional specialization of different hepatocyte populations[J].Physiol Rev 69: 708-764,1989.
[13]Flatt Jp. On the macimal possible rate of ketogenesis[J].Diabetes 21:50-53, 1972.
[14]Garber Aj, Menzel Ph, Boden G, et al. Hepatic ketogenesis and gluconeogenesis in humans[J].J Clin Invest 54: 981-989,1974.
[15]Serra D, Casals N, Asins G, et al. Regulation of mitochondrial 3-hydroxy-3- methylglutaryl-coenzyme A synthase protein by starvation, fat feeding and diabetes[J]. Arch Biochem Biophys 307:40-45,1993.
[16]Thumelin S, Forestier M, Girard J, et al. Developmental changes in mitochondrial-3- hydroxyl-3-mentylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney[J].Biochem J 292: 493-496,1993.
[17]Des Rosiers C, David F, Garneau M, et al. Nonhomogeneous labeling of liver mitochondrial acetyl-CoA[J].J Biol Chem 266:1574-1578,1991.
[18]Ayte J, Gil-Gomez G, Haro D, et al. Rat mitochondrial and cytosolic 3- hydroxy-3-methylglutaryl-CoA synthases are encoded by two different genes[J].Proc Natl Acad Sci(USA)87:3874-3878,1990.
[19]Boukaftane Y, Duncan A, Wang S, et al. Human mitochondrial HMG CoA synthase(mHS): liver cDNA and partial genomic cloning, chromosome mapping to 1p12-13 and possible role in vertebrate evolution[J].Genomics23:552-559, 1994
[20]Ashmarina Li, Rusnak N, Miziorko Hm, et al. 3-hydroxy-3- methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes[J].J Biol Chem 269: 31929-31932,1994.
[21]Krisans Sk. The role of peroxisomes in cholesterol metabolism[J].Am J Respir Cell Mol Biol7: 358-364,1992.
[22]Pardridge Wm. Blood-brain barrier transport of glucose, free fatty acids and ketone bodies. In: Vranic M, Efendic S, Hollenberg Ch, eds. Fuel homeostasis and the nervous system. New York: Plenum Press,43-53,1991.
[23] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase[J].Am. J. Physiol. Heart.Circ. Physiol. 281, H2289– H2294,2001.
[24] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA-transferase in rats after endotoxin administration[J].Proc. Natl. Acad. Sci. (USA) 98, 7146– 7151,2001.
[25] Uchida Y, Izai K, Orii T. Hashimoto T: Novel fatty acid beta-oxidation enzymes in rat liver mitochondria[J].J Biol Chem 267: 1034-1041,1992.
[26] C. Holm, T. Osterlund, H. Laurell, J.A. Contreras, Molecular mechanisms regulating hormo ne-sensitive lipase and lipolysis[J].Annu. Rev. Nutr. 20,365–393,2000.
[27] F.B. Kraemer, W.J. Shen, Hormone-sensitive lipase: control of intracellular tri- (di-) acylgl- ycerol and cholesteryl ester hydrolysis[J].J. Lipid. Res. 43,1585– 1594, 2002.
[28] W.J. Shen, Y. Liang, R. Hong, et al. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase[J].J. Biol. Chem. 276,49443–49448,2001.
[29] A.K. Saha, A.J. Schwarsin, R. Roduit, et al.Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta-D- ribofuranosi-de[J].J. Biol. Chem. 275 ,24279–24283,2000.
[30] Abu-Elheiga, M.M. Matzuk, K.A. Abo-Hashema, et al. Continuous fatty acid oxidat -ion and reduced fat storage in mice lacking acetyl-CoA carboxylase 2[J].Science 291, 2613–2616, 2001.
[31]Roach Pj. Multisite and hierarchal protein phosphorylation[J].J Biol Chem266: 14139-14142, 1991.
[32]Holm C, Davis Rc, Fredrickson G,et al. Expression of biologically active hormone-sensitive lipase in mammalian(COS) cells[J].FEBS Lett285:139-144,1991.
[33]Mabrouk Gm, Helmy Im, Thampsy Kg, et al. Acute hormonal control of acetyl-CoA carboxylase[J].J Biol Chem265:6330-6338,1990.
[34]Witters La, Kemp Be. Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5’-AMP-activated protein kinase[J].J Biol Chem267:2864-2867,1992.
[35]Gil-Gomez G, Ayte J, Hegardt Fg. The rat mitochondrial 3-hydroxy-3- methylglutaryl-coenzyme A-synthase gene contains elements that mediate itsmultihormonal regulation and tissue specificity[J].Eur J Biochem214:773-779,1993.
[36]Moir Am, Zammit Va. Rapic switch of hepatic fatty acid metabolism from oxidation to esterification during diurnal feeding of meal-fed rats correlates with changes in the properties of acetyl-CoA carboxylase, but not of carnitine palmitoyltransferase I[J]. Biochem J291:241-246,1993.
[37]Valera A, Pelegring M, Asins G, et al. Overexpression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in transgenic mice causes hepatic hyperketogenesis[J].J Biol Chem269:6267-6270, 1994.
[38]Galanello R, Cao A, Olivieri N. Induction of fetal hemoglobin in the presence of increased 3-hydroxybutyric acid associated with beta-ketothiolase deficiency[J].N Engl J Med331:746-747, 1994.
[39]Yudkoff M, Daikhin Y, Nissim I, et al .Effects of ketone bodies on astrocyte amino acid metabolism[J].J Neurochem 69: 682-692,1997.
[40]Yudkoff M, Daikhin Y, Nissim I, et al.Brain amino acid metabolism and ketosis[J].J Neurosci Res 66: 272-281,2001.
[41]Nehlig A, Pereira De Vasconcelos A. Glucose and ketone body utilization by the brain of neonatal rats[J].Prog Neurobiol40:163-221,1993.
[42]Auestad N, Fisher R, Chiappelli F,et al. Growth and development of brain of artificially reared hypoketonemic rat pups[J].Proc Soc Exp Biol Med195:335-344,1990.
[43]Gasch At. Use of the traditional ketogenic diet for treatment of intractable epilepsy[J].J Am Diet Assoc90:1433-1434,1990.
[44]Shih Ve, Mandell R, Sheinhait I. General metabolic screening tests. In:Hommes Fa,ed. Techniques in diagnostic human biochemical genetics: a laboratory manual. New York: Wiley -Liss,45-68,1991.
[45]Foster Dw. Diabetes mellitus. In: Wilson Jd, Braunwald E, Isselbacher Kj, et al, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill, Inc,1739- 1759,1991.
[46]Girard J, Ferre P, Pegorier J-P, et al. Adaptations of glucose and fatty acid metabolisu during perinatal period and suckling-weaning transition[J].Physiol Rev72: 507-562,1992.
[47]Bonnefont Jp, Specola Nb, Vassault A, et al. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states[J].Eur J Pediatr150:80-85,1990.
[48] P. Mukherjee, M.M. El Abbadi, J.L. Kasperzyk, et al. Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model[J].Br. J.Cancer 86 (10) :1615–1621,2002.
[49] Sullivan PG, Rippy NA, Dorenbos K, et al.The ketogenic diet increases mitochondrial uncoupling protein levels and activity[J].Ann Neurol55: 576-580,2004.
[50]Foster Dw. Eating disorders: obesity, anorexia nervosa and bulimia nervosa. In: Wilson Jd, Foster Dw, eds. Williams textbook of endocrinology. Philadelphia: W.B.Saunders Company, 1335- 1365,1992
[51]Aynsley-Green A, Mcgann A, Deshpande S: Control of intermediary metabolism in childhood with special reference to hypoglycaemia and growth hormone[J].Acta Paediatr Scand377:43-52, 1991.
[52]Fulop M. Alcoholi ketoacidosis[J].Endocrine Clin North Am889:209-219, 1993.
[53]Willems Pj, Gerver Wjm, Berger R, et al. The natural history of liver glycogenosis due to phosphrylase kinase deficiency: a longitudinal study of 41 patients[J]. Eur J Pediatr149:268-271, 1990.
[54]Labrune P, Chalas J, Baussan C, et al. Tolerance to prolonged fasting in two children with type Iglycogen storage disease[J].J Inherit Metab Dis16:1044- 1045,1993.
[55]Nakai A, Shigematsu Y, Liu Yy, et al. Urinary sugar phosphates and related organic acids in fructose-1.6-diphosphatase deficiency[J].J Inherit Metab Dis16:408- 418, 1993.
[56]Foster Dw, Rubenstein Ah. Hypoglycemia. In: Wilson Jd, Braunwald E, Isselbacher Kj et al. eds. Harrison’s principles of internal medicine New York: McGraw-Hill Inc.1759-1765,1991.
[57]Saudubray J-M, Mitchell Ga, et al. Approach to the patient with a fatty acid oxidation disorder In: Coates Pm, Tanaka K, eds. New development in fatty acid oxidation. New York: Wiley-Liss Inc.271-288,1992.
[58]Coates Pm, Stanley Ca. Inherited disorder of mitochondrial fatty acidoxidation[J].Prog Liver Dis10:123-138,1992
[59]Hale De, Bennett Mj. Fatty acid oxidation disorders: a new class of metabolic diseases[J].J Pediatr121:1-11,1992.
[60]Ozaki N, Ringe B, Gubernatis G, et al. Changes in energy substrates in relation to arterial ketone body ratio after human orthotopic liver transplantation[J]. Surgery113: 403-409. 1993.
[61]Yamaoka Y, Taki Y, Gibernatis G, et al. Evaluation of the liver graft before procurement: significance of arterial ketone body ratio in brain-dead patients[J].Transplant Int3:78-81,1990.
[62]Iwata S, Ozawa Z, Shimahara Y, et al. Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction[J].Gastroenterology 100:1371-1378,1991.
[63]Ozand Pt, Aqeel Aal, Gascon G, et al. 3-hydroxy-3- methylglutaryl- coenzyme A(HMG-CoA) lyase deficiency in Saudi Arabia[J].J Inherit Metab Dis14:174-188,1991.
[64]Thompson Gn, Chalmers Ra, Halliday D. The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria[J].Eur J Pediatr149:346-350, 1990.
[65]Mttchell Ga, Lamvert M, Tanguay Rm. Hypertyrosinemia. In: Scriver Cr, Beaudet A, Sly W, Valle D,eds. The metabolic basis of inherited disease. New York: McGraw-Hill,1995.
[66]Perez-Cerda, Merinero B, Sanz P, et al. A new case of succinyl- CoA: acetoacetate transferase deficiency[J].J Inherit Metab Dis15:371-373,1992.
[67]Sovik O. Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: an inborn error of isoleucine and ketone body metabolism[J].J Inherit Metab Dis16:46- 54,1993.
[68]Fukao T, Yamaguchi S, Kano M, et al. Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency[J].J Clin Invest86: 2086-2092,1990.
[69]Fukao T, Yamaguchi S, Orii T,et al. Molecular basis of beta- ketothiolase deficiency:mutations and polymorphisms in the human mitochondrial acetoacdtyl-coenzyme A thiolase gene[J].Human Mutation5:113-120,1995.
[70]Yamaguchi S, Fukao T, Song X-Q, et al. A preliminary study for cytosolic acetoacetyl- CoA thiolase(CT) deficiency: preparation of anti-CT antibody and cloning for human CT cDNA. Proceedings of the Sixth International Symposium of Inborn Errors of Metabolism(Abstr.):208, 1994.
[71]Kamijo T, Wanders Rj, Saudubray Jm, et al. Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients[J].J Clin Invest93:1740-1747,1994.
[72]Quant Pa. Experimental application of top-down control analysis to metabolic systems[J].Trends Biochem Sci18:26-30,1993.
[73]Quant Pa, Robin D, Rroin P, et al. A top-down control analysis in isolated rat liver mitochondria: can the 3-hydroxy-3-methylglutaryl-CoA pathway be rate-controlling for ketogenesis[J].Biochim Biophys Acta1156:135-143, 1993.
[2] J.T. Tildon, M. Cornblath, Succinyl-CoA:3-ketoacid CoA transferase deficiency: a cause for ketoacidosis in infancy[J].Clin. Invest. 1972(51):493–498.
[3] S. Kassovska-Bratinoba, T. Fukao, X.Q. Song, et al, Succinyl CoA:3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient[J]. Am. J. Hum. Genet.1996(59) :519– 528.
[4] X.Q. Song, T. Fukao, G.A. Mitchell, et al, Succinyl-CoA: 3-ketoacid coenzyme A transferase (SCOT): development of an antibody to human SCOT and diagnostic use in hereditary SCOT deficiency.[J]Biochim. Biophys.Acta 1997(1360): 151–156.
[5] X.Q. Song, T. Fukao, H. Watanabe, H. et al, Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings.[J]Hum. Mutat.1998(12):83–88.
[6] T. Fukao, G.A. Mitchell, X.Q. Song, H. Nakamura, et al, Succinyl-CoA: 3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations.[J]Genomics 2000(68):144–151.
[7] G.T.Berry, T. Fukao, G.A. Mitchell, et al, Neonatal hypoglycemia in severe succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency.[J]Inherit.Metab. Dis. 2000(24):587–595.
[8] N. Longo, T. Fukao, R. Singh, et al, Succinyl-CoA:3-keto acid transferase (SCOT) deficiency in a new patient homozygous for an R217X mutation.[J]Inherit. Metab. Dis. 2004(27):691–692.
[9] T. Fukao, H. Shintaku, R. Kusubae, et al, Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA transferase (SCOT) do not show permanent ketosis.[J]Pediatr. Res.2004(56):858–863.
[10]Toshiyuki Fukao, Satomi Sakurai, et al. A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency.[J]Mol Genet Metab.2006(89):280-282.
[11] Fukao T, Kursula P, et al.Identification and characterization of a temperature- sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(29):216-221.
[12] Keitaro Yamada,Toshiyuki Fukao, et. Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(90):291-297.
[13] Mitchell GA, Fukao T . Inborn errors of ketone body catabolism. In: Scriver CR,Beaudet AL, Sly WS, Valle D (eds) Metabolic and Molecular Bases of Inherited Disease, 8th Ed. McGraw-Hill, New York,2001 pp 2327–2356.
[14] Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.1992,330- 340.
[15] Balasse Eo, Fery F. Ketonee body production and disposal: effects of fasting, diabetes and exercise.[J]Diabetes Metab Rev 1989(5):247-270.
[16] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase.[J]Am. J. Physiol. Heart. Circ. Physiol. 2001(281):2289–2294.
[17] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA- transferase in rats after endotoxin administration,Proc. Natl. Acad. Sci. (USA)2001(98): 7146–7151.
[18] Wahle E and Keller W. The biochemistry of 3’-end cleavage and polyadenil- ation RNA precursors.[J]Annu. Rev. Biochem, 1992(61): 419-440.
[19] Sacha Kassovska-Bratinova, Toshiyuki Fukao, Xiang-Qian Song. Succinyl CoA:3-Oxoacid CoA Transferase (SCOT): Human cDNA Cloning, Human Chromosomal Mapping to 5pl 3, and Mutation Detection in a SCOT-Deficient Patient.[J]Am. J. Hum.Genet. 1996(59):519-528.
[20]Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.1992,330-340.
[21] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase.[J]Am. J. Physiol. Heart. Circ. Physiol. 2001(281):2289–2294.
[22] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA- transferase in rats after endotoxin administration,Proc. Natl. Acad. Sci. (USA) 2001 (98): 7146–7151.
[23] Spector Aa:Fatty acid binding to plasma albumin.[J]Lipid Res 1975(15):165-179.
[24]Ockner Rk, Kaikaus Rm, Bass Nm: Fatty acid bingding proteins: recent concepts of regulation and function. In: Coates P, Tanaka K eds. New development in fatty acid oxidation. New York: Wihey-Liss, Inc.1992,189-204.
[25]Stanley Ca: Plasma and mitochondrial membrane carnitine transport defedts. In: Coates P, Tanaka K, eds. New developments in fatty acid oxidation. New York: Wiley-Liss, Inc. 1992,289-300.
[26] Uchida Y, Izai K, Orii T. Hashimoto T: Novel fatty acid beta-oxidation enzymes in rat liver mitochondria.[J]Biol Chem 1992(267):1034-1041.
[27]Alessandra Kupper Cardozo, Linda De Meirleir, et al. Analysis of Exonic Mutations Leading to Exon Skipping in Patients with Pyruvate Dehydrogenase E1a Deficiency.[J]Pediatr. Res. 2000(48):748–752.
[28] Keitaro Yamada,Toshiyuki Fukao, et al. Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.[J]Mol Genet Metab. 2007(90):291-297
[29]Sakazaki H, Hirayama K, Murakami S, et al. A new Japaneses case of succinyl- CoA: 3-ketoacid CoA-transferase deficiency.[J]Inher Metab Dis 1995(18):323-325.
[30]Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev 2003(17):419–437.
[31] Krawczak M, Reiss J, Cooper DN. The mutational spectrum of single base pair substitutions in mRNA splice junctions of human genes: causes and consequences.[J]Hum Genet 1992(90):41–54.
[32]Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN.[J]Hum Mol Genet 2000(9):259–265.
[33]Blencowe, B. J. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases.[J]Trends Biochem Sci.2000(25):106–110.
[34] Clouet d’Orval BC, d’Aubenton Carafa YA, et al. RNA secondary structure repression of a muscle-specific exon in HeLa cell nuclear extracts.[J]Science1991 (252):1823–1828.
[35]Libri D, Piseri A, Fiszman MY .Tissue-specific splicing in vivo of the b-tropomyosin gene: dependence on an RNA secondary structure.[J]Science 1991(252): 1842–1845.
[36] Coleman TP, Roesser JR.RNA secondary structure: an important cis-element in rat calcitonin/CGRP pre-messenger RNA splicing.[J]Biochemistry1998(37):15941– 15950.
[37]Muro AF, Caputi M, Pariyarath R, et al.Regulation of fibronectin EDA exon alternative splicing: possible role of RNA secondary structure for enhancer display.[J]Mol Cell Biol 1999(19):2657–2671.
[38]Cartegni, L, Chew, S.L., and Krainer, A.R., Listening to silence and understanding nonsense exonic mutations that affect splicing.[J]Nat Rev Genet, 2000(3): 285-298.
[39]Alessandra Kupper Cardozo, Linda De Meirleir, et al. Analysis of Exonic Mutations Leading to Exon Skipping in Patients with Pyruvate Dehydrogenase E1a Deficiency.[J]Pediatr. Res. 2000(48):748–752.
[40]Maniatis, T. and Tasic, B, Alternative pre-mRNA splicing and proteome expansion in metazoans.[J]Nature. 2000(418): 236-243.
[41]Toshiyuki Fukao, Haruki Nakamura, Xiang-Qian Song, et al. Characteriztion of N93S, I312T, and A333P mission mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency.[J] Hum Muta.1998(12):245-254.
[1] G.A. Mitchell, T. Fukao, Inborn errors of ketone body metabolism, in: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle(Eds.), The Metabolic and Molecular Bases of Inherited Disease,McGraw-Hill, New York, 2001, pp. 2327–2356.
[2] Robingson Am, Willimson Dh, Physiological roles of ketone bodies as substrates and signals in mammalian tissues[J]. Physiol Rev 60:143-87,1980.
[3] Mcgarry Jd, Foster Dw: Rrgulation of hepatic fatty acid oxidation and ketone body production[J]. Ann Rev Biochem 49:395-420,1980.
[4] Mcgarry Jd, Woeltje Kf, Kuwajima M, et al. Regulation of ketogenesis snd the renaissance of carnitine palmitoyltransferanse[J].Diabetes Metab Rev5:271-284,1989.
[5] Balasse Eo, Fery F. Ketonee body production and disposal: effects of fasting, diabetes and exercise[J].Diabetes Metab Rev 5:247-270,1989.
[6]Williamson Dh. Ketone body production and metabolism in the fetus and newborn. In: Polin Ra, Fox Ww, eds. Fetal and neonatal physiology. Philadelphia: W.B. Saunders Co.330-340,1992
[7] Nosadini R, Avogaro A, Dofia A, et al. Ketone body metabolism: a physiological and clinical overview[J].Diabetes Metab Rev 5:299-319,1989.
[8] Guthrie Jp, Jordan F. Amine-catalyzed decarboxylation of acetoacetic acid. The rate constant for decarboxylation of beta-immino acid.[J]. Am Chem Soc 94: 9136-9141, 1972
[9] Seymour KJ, Bluml S, Sutherling J, et al. Identi￠cation of cerebral acetone by H-MRS in patients with epilepsy controlled by ketogenic diet[J]. MAGMA 8:33-42,1999.
[10] Likhodii SS, Serbanescu I, Cortez MA,et al.Anti-convulsant properties of acetone, a brain ketone elevated by the ketogenic diet[J].Ann Neurol54: 219-226,2003.
[11]Newsholme Ea, Leech Ar. Biochemistry for the medical sciences. New York: John Wiley &Sons, 1983.
[12]Jungermann K, Katz N. Functional specialization of different hepatocyte populations[J].Physiol Rev 69: 708-764,1989.
[13]Flatt Jp. On the macimal possible rate of ketogenesis[J].Diabetes 21:50-53, 1972.
[14]Garber Aj, Menzel Ph, Boden G, et al. Hepatic ketogenesis and gluconeogenesis in humans[J].J Clin Invest 54: 981-989,1974.
[15]Serra D, Casals N, Asins G, et al. Regulation of mitochondrial 3-hydroxy-3- methylglutaryl-coenzyme A synthase protein by starvation, fat feeding and diabetes[J]. Arch Biochem Biophys 307:40-45,1993.
[16]Thumelin S, Forestier M, Girard J, et al. Developmental changes in mitochondrial-3- hydroxyl-3-mentylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney[J].Biochem J 292: 493-496,1993.
[17]Des Rosiers C, David F, Garneau M, et al. Nonhomogeneous labeling of liver mitochondrial acetyl-CoA[J].J Biol Chem 266:1574-1578,1991.
[18]Ayte J, Gil-Gomez G, Haro D, et al. Rat mitochondrial and cytosolic 3- hydroxy-3-methylglutaryl-CoA synthases are encoded by two different genes[J].Proc Natl Acad Sci(USA)87:3874-3878,1990.
[19]Boukaftane Y, Duncan A, Wang S, et al. Human mitochondrial HMG CoA synthase(mHS): liver cDNA and partial genomic cloning, chromosome mapping to 1p12-13 and possible role in vertebrate evolution[J].Genomics23:552-559, 1994
[20]Ashmarina Li, Rusnak N, Miziorko Hm, et al. 3-hydroxy-3- methylglutaryl-CoA lyase is present in mouse and human liver peroxisomes[J].J Biol Chem 269: 31929-31932,1994.
[21]Krisans Sk. The role of peroxisomes in cholesterol metabolism[J].Am J Respir Cell Mol Biol7: 358-364,1992.
[22]Pardridge Wm. Blood-brain barrier transport of glucose, free fatty acids and ketone bodies. In: Vranic M, Efendic S, Hollenberg Ch, eds. Fuel homeostasis and the nervous system. New York: Plenum Press,43-53,1991.
[23] I.V. Turko, S. Marcondes, F. Murad, Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA: 3-oxoacid CoA-transferase[J].Am. J. Physiol. Heart.Circ. Physiol. 281, H2289– H2294,2001.
[24] S. Marcondes, I.V. Turko, F. Murad, Nitration of succinyl-CoA:3-oxoacid CoA-transferase in rats after endotoxin administration[J].Proc. Natl. Acad. Sci. (USA) 98, 7146– 7151,2001.
[25] Uchida Y, Izai K, Orii T. Hashimoto T: Novel fatty acid beta-oxidation enzymes in rat liver mitochondria[J].J Biol Chem 267: 1034-1041,1992.
[26] C. Holm, T. Osterlund, H. Laurell, J.A. Contreras, Molecular mechanisms regulating hormo ne-sensitive lipase and lipolysis[J].Annu. Rev. Nutr. 20,365–393,2000.
[27] F.B. Kraemer, W.J. Shen, Hormone-sensitive lipase: control of intracellular tri- (di-) acylgl- ycerol and cholesteryl ester hydrolysis[J].J. Lipid. Res. 43,1585– 1594, 2002.
[28] W.J. Shen, Y. Liang, R. Hong, et al. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase[J].J. Biol. Chem. 276,49443–49448,2001.
[29] A.K. Saha, A.J. Schwarsin, R. Roduit, et al.Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta-D- ribofuranosi-de[J].J. Biol. Chem. 275 ,24279–24283,2000.
[30] Abu-Elheiga, M.M. Matzuk, K.A. Abo-Hashema, et al. Continuous fatty acid oxidat -ion and reduced fat storage in mice lacking acetyl-CoA carboxylase 2[J].Science 291, 2613–2616, 2001.
[31]Roach Pj. Multisite and hierarchal protein phosphorylation[J].J Biol Chem266: 14139-14142, 1991.
[32]Holm C, Davis Rc, Fredrickson G,et al. Expression of biologically active hormone-sensitive lipase in mammalian(COS) cells[J].FEBS Lett285:139-144,1991.
[33]Mabrouk Gm, Helmy Im, Thampsy Kg, et al. Acute hormonal control of acetyl-CoA carboxylase[J].J Biol Chem265:6330-6338,1990.
[34]Witters La, Kemp Be. Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5’-AMP-activated protein kinase[J].J Biol Chem267:2864-2867,1992.
[35]Gil-Gomez G, Ayte J, Hegardt Fg. The rat mitochondrial 3-hydroxy-3- methylglutaryl-coenzyme A-synthase gene contains elements that mediate itsmultihormonal regulation and tissue specificity[J].Eur J Biochem214:773-779,1993.
[36]Moir Am, Zammit Va. Rapic switch of hepatic fatty acid metabolism from oxidation to esterification during diurnal feeding of meal-fed rats correlates with changes in the properties of acetyl-CoA carboxylase, but not of carnitine palmitoyltransferase I[J]. Biochem J291:241-246,1993.
[37]Valera A, Pelegring M, Asins G, et al. Overexpression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in transgenic mice causes hepatic hyperketogenesis[J].J Biol Chem269:6267-6270, 1994.
[38]Galanello R, Cao A, Olivieri N. Induction of fetal hemoglobin in the presence of increased 3-hydroxybutyric acid associated with beta-ketothiolase deficiency[J].N Engl J Med331:746-747, 1994.
[39]Yudkoff M, Daikhin Y, Nissim I, et al .Effects of ketone bodies on astrocyte amino acid metabolism[J].J Neurochem 69: 682-692,1997.
[40]Yudkoff M, Daikhin Y, Nissim I, et al.Brain amino acid metabolism and ketosis[J].J Neurosci Res 66: 272-281,2001.
[41]Nehlig A, Pereira De Vasconcelos A. Glucose and ketone body utilization by the brain of neonatal rats[J].Prog Neurobiol40:163-221,1993.
[42]Auestad N, Fisher R, Chiappelli F,et al. Growth and development of brain of artificially reared hypoketonemic rat pups[J].Proc Soc Exp Biol Med195:335-344,1990.
[43]Gasch At. Use of the traditional ketogenic diet for treatment of intractable epilepsy[J].J Am Diet Assoc90:1433-1434,1990.
[44]Shih Ve, Mandell R, Sheinhait I. General metabolic screening tests. In:Hommes Fa,ed. Techniques in diagnostic human biochemical genetics: a laboratory manual. New York: Wiley -Liss,45-68,1991.
[45]Foster Dw. Diabetes mellitus. In: Wilson Jd, Braunwald E, Isselbacher Kj, et al, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill, Inc,1739- 1759,1991.
[46]Girard J, Ferre P, Pegorier J-P, et al. Adaptations of glucose and fatty acid metabolisu during perinatal period and suckling-weaning transition[J].Physiol Rev72: 507-562,1992.
[47]Bonnefont Jp, Specola Nb, Vassault A, et al. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states[J].Eur J Pediatr150:80-85,1990.
[48] P. Mukherjee, M.M. El Abbadi, J.L. Kasperzyk, et al. Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model[J].Br. J.Cancer 86 (10) :1615–1621,2002.
[49] Sullivan PG, Rippy NA, Dorenbos K, et al.The ketogenic diet increases mitochondrial uncoupling protein levels and activity[J].Ann Neurol55: 576-580,2004.
[50]Foster Dw. Eating disorders: obesity, anorexia nervosa and bulimia nervosa. In: Wilson Jd, Foster Dw, eds. Williams textbook of endocrinology. Philadelphia: W.B.Saunders Company, 1335- 1365,1992
[51]Aynsley-Green A, Mcgann A, Deshpande S: Control of intermediary metabolism in childhood with special reference to hypoglycaemia and growth hormone[J].Acta Paediatr Scand377:43-52, 1991.
[52]Fulop M. Alcoholi ketoacidosis[J].Endocrine Clin North Am889:209-219, 1993.
[53]Willems Pj, Gerver Wjm, Berger R, et al. The natural history of liver glycogenosis due to phosphrylase kinase deficiency: a longitudinal study of 41 patients[J]. Eur J Pediatr149:268-271, 1990.
[54]Labrune P, Chalas J, Baussan C, et al. Tolerance to prolonged fasting in two children with type Iglycogen storage disease[J].J Inherit Metab Dis16:1044- 1045,1993.
[55]Nakai A, Shigematsu Y, Liu Yy, et al. Urinary sugar phosphates and related organic acids in fructose-1.6-diphosphatase deficiency[J].J Inherit Metab Dis16:408- 418, 1993.
[56]Foster Dw, Rubenstein Ah. Hypoglycemia. In: Wilson Jd, Braunwald E, Isselbacher Kj et al. eds. Harrison’s principles of internal medicine New York: McGraw-Hill Inc.1759-1765,1991.
[57]Saudubray J-M, Mitchell Ga, et al. Approach to the patient with a fatty acid oxidation disorder In: Coates Pm, Tanaka K, eds. New development in fatty acid oxidation. New York: Wiley-Liss Inc.271-288,1992.
[58]Coates Pm, Stanley Ca. Inherited disorder of mitochondrial fatty acidoxidation[J].Prog Liver Dis10:123-138,1992
[59]Hale De, Bennett Mj. Fatty acid oxidation disorders: a new class of metabolic diseases[J].J Pediatr121:1-11,1992.
[60]Ozaki N, Ringe B, Gubernatis G, et al. Changes in energy substrates in relation to arterial ketone body ratio after human orthotopic liver transplantation[J]. Surgery113: 403-409. 1993.
[61]Yamaoka Y, Taki Y, Gibernatis G, et al. Evaluation of the liver graft before procurement: significance of arterial ketone body ratio in brain-dead patients[J].Transplant Int3:78-81,1990.
[62]Iwata S, Ozawa Z, Shimahara Y, et al. Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction[J].Gastroenterology 100:1371-1378,1991.
[63]Ozand Pt, Aqeel Aal, Gascon G, et al. 3-hydroxy-3- methylglutaryl- coenzyme A(HMG-CoA) lyase deficiency in Saudi Arabia[J].J Inherit Metab Dis14:174-188,1991.
[64]Thompson Gn, Chalmers Ra, Halliday D. The contribution of protein catabolism to metabolic decompensation in 3-hydroxy-3-methylglutaric aciduria[J].Eur J Pediatr149:346-350, 1990.
[65]Mttchell Ga, Lamvert M, Tanguay Rm. Hypertyrosinemia. In: Scriver Cr, Beaudet A, Sly W, Valle D,eds. The metabolic basis of inherited disease. New York: McGraw-Hill,1995.
[66]Perez-Cerda, Merinero B, Sanz P, et al. A new case of succinyl- CoA: acetoacetate transferase deficiency[J].J Inherit Metab Dis15:371-373,1992.
[67]Sovik O. Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: an inborn error of isoleucine and ketone body metabolism[J].J Inherit Metab Dis16:46- 54,1993.
[68]Fukao T, Yamaguchi S, Kano M, et al. Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency[J].J Clin Invest86: 2086-2092,1990.
[69]Fukao T, Yamaguchi S, Orii T,et al. Molecular basis of beta- ketothiolase deficiency:mutations and polymorphisms in the human mitochondrial acetoacdtyl-coenzyme A thiolase gene[J].Human Mutation5:113-120,1995.
[70]Yamaguchi S, Fukao T, Song X-Q, et al. A preliminary study for cytosolic acetoacetyl- CoA thiolase(CT) deficiency: preparation of anti-CT antibody and cloning for human CT cDNA. Proceedings of the Sixth International Symposium of Inborn Errors of Metabolism(Abstr.):208, 1994.
[71]Kamijo T, Wanders Rj, Saudubray Jm, et al. Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients[J].J Clin Invest93:1740-1747,1994.
[72]Quant Pa. Experimental application of top-down control analysis to metabolic systems[J].Trends Biochem Sci18:26-30,1993.
[73]Quant Pa, Robin D, Rroin P, et al. A top-down control analysis in isolated rat liver mitochondria: can the 3-hydroxy-3-methylglutaryl-CoA pathway be rate-controlling for ketogenesis[J].Biochim Biophys Acta1156:135-143, 1993.