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

肉碱缺乏下幼年内脏脂肪变性小鼠尿素循环酶基因表达抑制机制。

基本信息

批准号：
08670182
负责人：
SAHEKI Takeyori
金额：
$ 1.41万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

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.

幼年内脏脂肪变性（JVS）小鼠是由金泽大学医学部发现的肉毒碱缺乏的动物模型，并且患有脂肪肝、低血糖、高氨血症、生长迟缓和心脏肥大。我们已经表明，小鼠的高氨血症是由于肝脏中所有尿素循环酶的活性和蛋白质量降低所致，这是由酶基因的转录抑制引起的。我们还表明，JVS小鼠的所有症状都可以通过给予肉毒碱完全改善。在这项研究中，使用primay培养的大鼠肝细胞，我们报告说，长链脂肪酸抑制诱导的尿素循环酶，氨甲酰磷酸合成酶I（CPS-I）和氨基琥珀酸合成酶，地塞米松。添加长链脂肪酸也引起AP-1 DNA结合活性的激活，在培养的肝细胞中，发现在肝脏JVS小鼠。这些发现，加上JVS小鼠血浆游离脂肪酸的增加，强烈表明，在肉毒碱缺乏下长链脂肪酸的积累是体内尿素循环酶基因抑制的主要原因，导致高氨血症。此外，我们发现，我们克隆的小鼠CPS-I基因的启动子和增强子的核苷酸序列与大鼠的基因有很高的同源性，特别是，在增强子区域有两个AP-1位点。我们现在正在研究AP-1位点在长链脂肪酸引起的基因表达抑制中的作用。