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Mechanism of suppression of urea cycle enzyme gene expression under carnitine deficiency in juvenile visceral steatosis mice.

Research Project

Project/Area Number 08670182
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKagoshima University

Principal Investigator

SAHEKI Takeyori  Kagoshima University Faculty of Medicine Professor, 医学部, 教授 (10056070)

Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1996: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsFatty acid / Carnitine / Carbamoylphosphate synthetase / Urea cycle / Gene expression / Hyperammonemia / カルバミルリン酸合成酵素(Carbamylphosphate synthetase)
Research Abstract

Juvenile visceral steatosis (JVS) mice are an animal model of carnitine deficiency, discovered at Kanazawa University, Faculty of Medicine, and suffer from fatty liver, hypoglycemia, hyperammonemia, growth retardation and cardiac hypertrophy. We have shown that hyperammonemia of the mice results from a decrease in the activity and protein amount of all urea cycle enzymes in the liver, caused by suppressed transcription of the enzyme genes. We also showed that all of the symptoms of JVS mice can be completely ameliorated by the administration of carnitine. In this research using primay cultured rat hepatocytes, we report that long-chain fatty acids suppressed the induction of urea cycle enzymes, carbamoylphosphate synthetase I (CPS-I) and argininosuccinate synthetase, by dexamethasone. The addition of long-chain fatty acids also caused activation of AP-1 DNA binding activity in the cultured hepatocytes, as found in the liver JVS mice. These findings, together with the increase of plasma free fatty acids in JVS mice, strongly suggest that the accumulation of long-cahin fatty acids under carnitine deficiency is the major cause of suppression of urea cycle enzyme genes in vivo, resulting in hyperammonemia. Furthermore, we found that nucleotide sequences of promoter and enhancer of mouse CPS-I gene we cloned have a high homology with those of the rat gene and that, notably, there is two AP-1 sites in the enhancer region. We are now investigating the role of the AP-1 sites in the suppression of the gene expression caused by long-chain fatty acids.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Tomomura M: "Long-chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action." FEBS Lett.399. 310-312 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tomomura M: "Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient hjuvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood." J.Biochem.121. 172-177 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 堀内 正久: "代謝異常患者の病態形成における遺伝子発現異常-全身性カルニチン欠乏マウスの知見から-" 生化学. 68. 1654-1657 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nakajima T: "The effed of carnitine on ketogenesis in perfused livers from juvenile visceral steatosis mice with systemic carnitine deficiency." Pediatr.Res.42. 108-113 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 佐伯 武頼: "2種の疾患モデル動物における高アンモニア血症発症機構-尿素サイクル酵素欠損マウスとカルニチン欠損マウス-" 病理と臨床. 15. 800-805 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Saheki T: "Advances in Cirrhosis,Hyperammonemia,and Hepatic Encephalopathy" Plenum Publishing Corporation, 281 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M Tomomura: "Long-chain fatty acids suppress the induction of urea cycle enzyme genes by ghucocorticoid action." FEBS Lett.399. 310-312 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M Tomomura: "Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis (JVS) mice in infancy and during starvation in adulthood." J.Biochem.121. 172-177 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M Horiuchi: "Abnormal gene expression and regulation in jvs mice with systemic carnitine deficiency." Seikagaku. 68. 1654-1657 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T Nakajima: "The effect of carnitine on ketogenesis in perfused livers from juvenile visceral steatosis mice with systemic carnitine deficiency." Pediatr.Res.42. 108-113 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T Saheki: "Hyperammonemia in animal models, ornithine carbamoyltransferase-deficient mice and carnitine-deficient mice." Rinsyo to byouri. 15. 800-805 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] T Saheki: "Abnormal gene expression causing hyperammonemia in carnitine-deficient juvenile visceral steatosis (JVS) mice." Advances in Cirrhosis, Hyperammonemia, and Hepatic Encephalopathy. 159-172 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nakajima T: "The effect of carnitine on ketogenesis in perfused livers from juvenile visceral steatosis mice with systemic carnitine deficiency." Pediatr.Res.42. 108-113 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 佐伯武頼: "2種の疾患モデル動物における高アンモニア血症発症機構-尿素サイクル酵素欠損マウスとカルニチン欠損マウス-" 病理と臨床. 15. 800-805 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Saheki T: "Advances in Cirrhosis,Hyperammonemia,and Hepatic Encephalopathy" Plenum Publishing Corporation, 281 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tomomura M: "Long-chain fatty acids suppress the induction of urea cycle enzyme genes by glucocorticoid action." FEBS Lett.399. 310-312 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tomomura M: "Suppressed expression of the urea cycle enzyme genes in the liver of carnitine-deficient juvenile visceral steatosis(JVS)mice in infancy and during starvation in adulthood." J.Biochem.121. 172-177 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 堀内正久: "代謝異常疾患の病態形成における遺伝子発現異常-全身性カルニチン欠乏マウスの知見から-" 生化学. 68. 1654-1657 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Saheki T: "Procedings of International Ammoniagenesis Workshop Nutritional and Acid-Base Aspects of Amino Acid Metabolism" D.J.O'Donovan (in press), (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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