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S. Noguchi, Y. Ohba, and T. Oka

ABSTRACT

The role of epidermal growth factor (EGF) in liver regeneration was studied in mice after partial hepatectomy. Two weeks before partial hepatectomy, mice were sham-operated (control) or sialoadenectomized (removal of submandibular glands) to reduce plasma EGF levels. Sialoadenectomized mice showed low plasma EGF levels (29·7 ±6·6 pmol/l; mean ± s.e.m.) compared with controls (66·0±8·3 pmol/l). After partial hepatectomy, sialoadenectomized mice were treated with or without a daily s.c. injection of 5 μg EGF and the rate of DNA synthesis in the regenerating liver was monitored by [125I]iododeoxyuridine uptake. Control mice showed a sharp peak of DNA synthesis at 48 h after partial hepatectomy while sialoadenectomized mice showed a delayed and broad peak at 84 h. Treatment of sialoadenectomized mice with EGF (5 μg/mouse per day) completely restored the pattern of DNA synthesis so that a sharp peak appeared at 48 h. The total liver DNA content of the control mice (79·1±2·5% of the preoperative level; mean ± s.e.m.) was significantly (P < 0·01) higher than that of the sialoadenectomized mice (65·2±3·0%) 3 days after partial hepatectomy, but this difference disappeared on day 7 when liver regeneration was almost completed in both groups. Treatment of sialoadenectomized mice with EGF increased total liver DNA content (78·2±2·9%) to that of control mice on day 3 after partial hepatectomy. In addition, normal mice showed a rapid increase in plasma EGF levels at 1–8 h after partial hepatectomy, whereas sialoadenectomized mice showed low plasma EGF levels throughout the course of the experiment. These results suggest that EGF derived from the submandibular glands plays a role in promoting the early stage of liver regeneration.

Journal of Endocrinology (1991) 128, 425–431

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T. Noguchi, T. Sugisaki, T. Kanamatsu, I. Satoh, and N. Nishikawa

ABSTRACT

The prolactin-producing cells of the bovine anterior pituitary were found to contain a vasoactive intestinal polypeptide (VIP) immunoreactive substance, thus suggesting a role for VIP in the regulation of prolactin release.

The pituitaries of the dw and lit strains of mutant mice, congenitally deficient in prolactin-producing cells, and hyt mice, which were found to have reduced numbers of prolactin-producing cells, showed a markedly reduced VIP immunoreactivity. Hypothalamic VIP immunoreactivity, however, was found to be unchanged in the three strains of mutant mice, indicating that the high concentration of VIP in the hypothalamus does not derive from the adenohypophysis through retrograde flow. The deficiency in the mutant mice seems to be due to the lack of prolactin target cells in the pituitary.

J. Endocr. (1988) 118, 179–185

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T. Sugisaki, T. Yamada, K. Takamatsu, and T. Noguchi

ABSTRACT

Serum insulin-like growth factor-I (IGF-I) levels in lit (isolated GH deficiency), dw (panhypopituitarism), hyt (hypothyroidism) and cog (congenital goiter) mutant mice were found to be significantly lower than in control mice. In addition, liver and kidney IGF-I concentrations in mutants were also found to be significantly reduced compared with controls. These differences in IGF-I concentration were not observed in pg (genetic IGF receptor or post-receptor defect?) mice. These results indicated that serum IGF-I production is induced by thyroid hormones as well as by GH. Western blot analysis of serum IGF-binding protein (IGFBP) fractions revealed the following differences among the five mutants: the triplet of IGFBP-3 (42, 45 and 49 kDa) and IGFBP-4 (24 kDa) levels were significantly reduced. IGFBP-2 (32 kDa) levels were also reduced in the lit, hyt and cog mice, although the level in serum of dw mice was found to be greatly elevated. No differences in serum IGFBP levels were found in the pg mouse. Consequently, the ratio of IGFBP-3%: IGFBP-2% (the percentage of IGFBP-3 fraction of total IGFBP (IGFBP-3%) divided by that of IGFBP-2 (IGFBP-2%)) was decreased in GH-deficient mice but increased in hypothyroid mice, suggesting that IGFBP-3 and IGFBP-2 production in the liver is induced by GH and thyroid hormones respectively.

Journal of Endocrinology (1993) 138, 467–477

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T. Noguchi, M. Kudo, T. Sugisaki, and I. Satoh

ABSTRACT

The hyt mutant mouse used in this study has a hypoplastic thyroid gland and is characterized by retarded somatic growth, very low to undetectable levels of plasma thyroxine (T4), and increased levels of plasma thyroid-stimulating hormone (TSH). This congenital hypothyroid mouse is therefore an ideal model for studying the effects of thyroid hypofunction on the adenohypophysis.

The anterior pituitary of the hyt mouse appeared less granular than that of the normal control when viewed by light microscopy, owing to a decrease in the population of somatotrophs. Many cells, in various stages of transformation into 'thyroidectomy cells', were recognized by the appearance of the characteristic granules and dilated rough endoplasmic reticulum. In some cases, the enlarged rough endoplasmic reticulum also contained spherical electron-dense secretory granules. In addition there were many cells undergoing mitosis and these were identified as thyrotrophs by their characteristic granules.

Administration of T4 during the first 40 days of life prevented the abnormal changes in the hyt anterior pituitary.

A reduction in immunoreactive thyrotrophin-releasing hormone (TRH) levels was seen in the median eminence of the hyt mouse. Treatment with T4 restored this to normal, suggesting that the reduced TRH content of the hypothalamus of the mutant mouse may be due to T4 deprivation.

J. Endocr. (1986) 109, 163–168

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ZW Fu, T Kubo, K Sugahara, T Noguchi, and H Kato

We investigated the effects of vitamin A (VA) nutritional status on the levels of expression of retinoic acid (RA) receptor-beta (RARbeta) gene in the various tissues of Japanese quail. VA deficiency caused a significant decrease in the mRNA levels of brain, liver, heart, lung and kidney RARbeta2/beta4, whereas no change was observed in the level of testis RARbeta2 transcript. In contrast, reduction in the RARbeta1 transcript caused by VA depletion was observed only in the lung, remaining unchanged in the other tissues. The administration of RA to the VA-deficient quail rapidly induced the expression of RARbeta2/beta4 mRNAs in all the tissues examined, but RA increased the expression of RARbeta1 transcript in the liver, heart, lung and kidney at a lower magnitude. RA could not change the expression of the brain RARbeta1 transcript, while it induced the expression of the testis RARbeta1 mRNA in a temporal way. These results clearly indicate that VA nutritional status differently regulates the expression of RARbeta1 and RARbeta2/beta4 transcripts in a tissue-specific manner.

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M Imae, Y Inoue, Z Fu, H Kato, and T Noguchi

Hepatocyte nuclear factor-3 (HNF-3) belongs to a large family of forkhead transcription factors and is made up of three members (HNF-3alpha, -3beta and -3gamma). It has been shown that HNF-3 regulates a number of metabolically important genes. However, the mechanisms underlying this regulation of HNF-3 activity by hormones and nutrition have not yet been well elucidated. In attempting to explore the regulation of gene expression of HNF-3 members by physiological status, we analyzed the effects of insulin, dexamethasone and protein malnutrition on the hepatic mRNA level of each member. Male Wistar rats were fed on a 12% casein diet, 12% gluten diet (deficient in lysine and threonine) or a protein-free diet for 1 week. The protein-free diet and gluten diet caused a 3. 7-fold increase in HNF-3g mRNA in the liver and did not affect the mRNA level of either HNF-3alpha or HNF-3beta. Daily administration of dexamethasone caused the mRNA levels of HNF-3alpha and HNF-3beta to increase (2.3- and 1.4-fold, respectively), but had no effect on the HNF-3gamma mRNA level. In diabetic rats that had been injected with streptozotocin, an elevation of the hepatic mRNA levels of HNF-3beta and HNF-3gamma was observed (1.6-and 1.9-fold, respectively). Insulin replacement in the diabetic rats decreased both mRNA levels in a dose-dependent manner. HNF-3alpha mRNA was not affected by insulin status. These results show that the genes of the three members of the HNF-3 family respond differently to hormonal and nutritional factors suggesting that the activities of HNF-3 members are regulated, at least in part, by the levels of their gene expression.

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A Takenaka, K Komori, T Morishita, SI Takahashi, T Hidaka, and T Noguchi

To investigate the molecular mechanisms of increased transcription of the insulin-like growth factor-binding protein-1 (IGFBP-1) gene in dietary protein-deprived animals, the cis-acting sequence that is involved in this regulation was analyzed. We first showed that IGFBP-1 gene transcription was up-regulated by amino acid deprivation in cultured liver cell lines: H4IIE and HuH-7. Since HuH-7 cells showed a greater increase in IGFBP-1 mRNA in response to amino acid deprivation, this cell line was used in further experiments. Using a promoter function assay, we found that up-regulation of promoter activity responding to amino acid deprivation was abolished by deleting the region between -112 and -81 bp from the cap site from the gene construct. This cis-acting region includes the insulin-responsive element (IRE) and glucocorticoid responsive element (GRE) of IGFBP-1. In summary, the present observation suggests that the 32-bp (-112 to -81) in the IGFBP-1 gene 5' promoter region is involved in the induction of the IGFBP-1 gene in response to amino acid deprivation.

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Y Ito, M Ariga, S-I Takahashi, A Takenaka, T Hidaka, and T Noguchi

Abstract

The binding of insulin to its receptor rapidly induces intrinsic insulin receptor tyrosine kinase activity, resulting in tyrosine phosphorylation of various cytosolic substrates, such as insulin receptor substrate-1 (IRS-1) which, in turn, associates with a p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) followed by activation of this enzyme.

In the present study, we have examined these early steps of insulin signalling in rat liver in vivo after food ingestion. After fasting for 22 h, a 12% casein diet was available ad libitum throughout the 8-h experimental period. Plasma insulin concentrations increased within 45 min after feeding, reached a maximum at 1·5 h and gradually decreased until 8 h. Autophosphorylation of the insulin receptor β-subunit in liver was detected even during fasting and increased about 1·5-fold at 1·5 h after feeding. Basal tyrosine phosphorylation of IRS-1 was detectable during starvation, increased about twofold at 3 h after feeding and levels were maintained until 8 h. The content of the p85 subunit of PI 3-kinase associated with IRS-1 also increased after feeding in parallel with the changes in tyrosine phosphorylation of IRS-1.

Because tyrosine phosphorylation of the insulin receptor β-subunit and IRS-1 and the association of the p85 subunit of PI 3-kinase with IRS-1 in liver were closely correlated with the changes in the plasma concentration of insulin, we concluded that endogenous insulin secreted in response to eating caused these insulin-dependent intracellular changes in the liver.

Journal of Endocrinology (1997) 154, 267–273

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A Takenaka, M Mori, S Yamada, J Ohgane, S-I Takahashi, and T Noguchi

Abstract

The plasma concentration and liver mRNA content of IGF-I are regulated by the quantity and quality of dietary proteins. To determine whether the synthesis of IGF-binding proteins (BPs) is also affected by protein nutrition, we assessed plasma concentration, tissue mRNA content and liver transcription rate of each BP after rats were fed either a 12% casein or a protein-free diet for 1 week. Protein deprivation reduced the plasma concentration of IGFBP-3 and IGFBP-4 and increased that of IGFBP-1 and IGFBP-2. The mRNA content in tissues and liver transcription rates of IGFBP-3 and IGFBP-4 did not change in response to protein deprivation although their plasma concentrations decreased. The increased plasma IGFBP-1 and IGFBP-2 concentrations were explained by the increased mRNA content and transcription rate of their genes in the liver. Although IGFBP-1 mRNA was increased by protein deprivation not only in liver but also in kidney, IGFBP-2 mRNA was increased only in liver and did not increase in any other tissue examined. In addition, the liver mRNA content of the acid-labile subunit, which can form a ternary complex with IGFs and IGFBP-3, was not affected by protein deprivation. These results show that tissue-specific synthesis of each BP is regulated in a distinct way in response to protein deprivation.

Journal of Endocrinology (1996) 150, 33–41

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K. Kizuki, A. Kitagawa, M. Takahashi, H. Moriya, M. Kudo, and T. Noguchi

ABSTRACT

The localization of tissue kallikrein in the pituitary gland of rats was investigated by an immunohistochemical technique using antiserum against rat urinary kallikrein. Kallikrein-positive cells were detected in the anterior lobe of the pituitary of both male and female rats, but were not observed in the posterior lobe of the pituitary in either sex.

The kallikrein-positive cells in the anterior pituitary of female rats in oestrus were found to correspond to the prolactin-producing cells, whereas the cells producing GH, LH and ACTH were negative for kallikrein. It is possible, therefore, that the tissue kallikrein may be involved in the production of prolactin and not that of the other anterior pituitary hormones, such as GH, LH, FSH, ACTH and TSH.

Journal of Endocrinology (1990) 127, 317–323