Tomomura M, Imamura Y, Tomomura A, Horiuchi M, Saheki T
Department of Biochemistry, Faculty of Medicine, Kagoshima University, Japan.
Biochim Biophys Acta. 1994 Jul 18;1226(3):307-14. doi: 10.1016/0925-4439(94)90042-6.
Carnitine-deficient jvs mice expressed reduced levels of a group of genes which are preferentially expressed in the liver, including urea cycle enzyme genes (Biochim. Biophys. Acta 1138, 167-171, 1992). The expression of alpha-fetoprotein and aldolase A was elevated, indicating that the liver of jvs mice is undifferentiated or dedifferentiated (FEBS Lett. 311, 63-66, 1992). Studies of the hormone signal transduction pathway showed that serum cortisol and plasma glucagon levels of jvs mice were 2 and 3 times higher, respectively, than those of normal mice, and that the hormone binding activity of glucocorticoid receptor (GR) in the cytosol of jvs liver was 50% of normal mice, which reflected the amount of receptor protein in the cytosol. On the other hand, GR protein accumulated in the nuclear fraction in jvs mice. Exogenously administrated dexamethasone induced carbamoyl phosphate synthetase (CPS) and tyrosine aminotransferase (TAT) mRNAs in jvs mice, indicating that CPS and TAT genes in jvs mice are responsive to induction by glucocorticoid and cAMP. Analysis of transacting factors by gel retardation assay revealed that HNF-1, COUP-TF and SP-1 were detected at almost the same level in the hepatic nuclear fraction of jvs mice as in normal littermates, and C/EBP and CREB were a little higher in jvs mice, suggesting that these factors are probably not targets of jvs mutation causing abnormal gene expression in the liver. On the other hand, AP-1 binding activity was much higher in jvs mice from an early age, preceding the abnormal expression of urea cycle enzyme, and carnitine administration normalized AP-1 binding activity. We suggest that elevated AP-1 binding induced by carnitine deficiency is closely connected with the abnormal gene expression in the liver.
肉碱缺乏的jvs小鼠表达了一组在肝脏中优先表达的基因的水平降低，包括尿素循环酶基因（《生物化学与生物物理学报》1138卷，167 - 171页，1992年）。甲胎蛋白和醛缩酶A的表达升高，表明jvs小鼠的肝脏未分化或去分化（《欧洲生物化学学会联合会快报》311卷，63 - 66页，1992年）。对激素信号转导途径的研究表明，jvs小鼠的血清皮质醇和血浆胰高血糖素水平分别比正常小鼠高2倍和3倍，并且jvs肝脏细胞质中糖皮质激素受体（GR）的激素结合活性是正常小鼠的50%，这反映了细胞质中受体蛋白的量。另一方面，GR蛋白在jvs小鼠的细胞核部分积累。外源性给予地塞米松可诱导jvs小鼠中的氨甲酰磷酸合成酶（CPS）和酪氨酸转氨酶（TAT）mRNA，表明jvs小鼠中的CPS和TAT基因对糖皮质激素和cAMP的诱导有反应。通过凝胶阻滞试验对反式作用因子的分析表明，在jvs小鼠肝脏细胞核部分中检测到的HNF - 1、COUP - TF和SP - 1水平与正常同窝小鼠几乎相同，而C/EBP和CREB在jvs小鼠中略高，这表明这些因子可能不是导致肝脏中基因异常表达的jvs突变的靶点。另一方面，从幼年起，jvs小鼠中的AP - 1结合活性就高得多，早于尿素循环酶的异常表达，并且给予肉碱可使AP - 1结合活性正常化。我们认为，肉碱缺乏诱导的AP - 1结合升高与肝脏中的异常基因表达密切相关。
