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Yutaka Takahashi,
Keiji Iida,
Kentaro Takahashi, Shiro Yoshioka,
Hidenori Fukuoka,
Ryoko Takeno,
Mari Imanaka,
Hitoshi Nishizawa,
Michiko Takahashi,
Yasushi Seo,
Yoshitake Hayashi,
Takuma Kondo,
Yasuhiko Okimura,
Hidesuke Kaji,
Riko Kitazawa,
Sohei Kitazawa,
Kazuo Chihara
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ABSTRACT: Nonalcoholic steatohepatitis (NASH) is an emerging progressive hepatic disease and demonstrates steatosis, inflammation, and fibrosis. Insulin resistance is a common feature in the development of NASH. Molecular pathogenesis of NASH consists of 2 steps: triglyceride accumulation in hepatocytes with insulin resistance and an enhanced oxidative stress caused by reactive oxygen species. Interestingly, NASH demonstrates a striking similarity to the pathologic conditions observed in adult growth hormone deficiency (AGHD). AGHD is characterized by decreased lean body mass, increased visceral adiposity, abnormal lipid profile, and insulin resistance. Moreover, liver dysfunctions with hyperlipidemia and nonalcoholic fatty liver disease (NAFLD) are frequently observed in patients with AGHD, and it is accompanied by metabolic syndrome.
We studied a case diagnosed as NASH with hyperlipidemia in AGHD. The effect of GH-replacement therapy on the patient was analyzed.
Six months of GH-replacement therapy in the patient drastically ameliorated NASH and the abnormal lipid profile concomitant with a marked reduction in oxidative stress.
These results suggest that GH plays an essential role in the metabolic and redox regulation in the liver.
Gastroenterology 04/2007; 132(3):938-43. · 11.68 Impact Factor
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ABSTRACT: Excess and deficit of growth hormone (GH) both affect cardiac architecture as well as its function. To date, experimental and clinical studies have reported that GH has an inotropic effect on animal and human heart, however, it remains controversial whether GH is applicable to the treatment for the patients with chronic heart failure. Also, the mechanism by which GH exerts these biological effects on the heart is not well understood. In this study, we attempted to specify the genes regulated by GH in the heart of spontaneous dwarf rat using a microarray analysis. We found that soluble forms of guanylate cyclase, cofilin1, and thymosin beta4 mRNA were up-regulated in the heart by GH treatment. On the other hand, acyl-CoA synthetase, aldosterone receptor, myosin regulatory light chain, troponin T, laminA, and beta-actin mRNA were down-regulated. These results suggest GH regulates essential molecules that regulate structural, contractile, remodeling, and regenerative functions. Collectively, our data indicate a new integrative understanding for the biological effects of GH on cardiac function.
Biochemical and Biophysical Research Communications 04/2006; 341(1):88-93. · 2.48 Impact Factor
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ABSTRACT: It is well known that growth hormone (GH) is involved in the development of arteriosclerosis in which vascular smooth muscle cells (VSMC) play an important role. In this study, we attempted to specify the genes up- or down-regulated by recombinant human GH (rhGH) in VSMC using a differential display method. We found that rhGH increased cytochrome oxidase subunit II/III mRNA in VSMC. Furthermore, the mRNA for mitochondrial transcription factor 1 (mtTF1), which stimulates the expression of cytochrome oxidase subunit II/III, was found to be up-regulated by rhGH in a dose dependent manner using a quantitative PCR method. On the other hand, IGF-I alone did not change mtTF1 mRNA levels. In rat L6 myoblasts and rat H4-II-E hepatocytes, rhGH did not change mtTF1 mRNA levels. Pretreatment with a JAK2 inhibitor AG490 (10 nM) and a MEK inhibitor PD98059 (10 microM) suppressed rhGH-induced rise in mtTF1 mRNA levels of VSMC to the control levels. Pretreatment with a PI-3kinase inhibitor wortomannin (1 nM) did not suppress rhGH-induced rise in mtTF1 mRNA levels. These findings suggest that GH up-regulates mtTF1 mRNA levels through JAK2 and MEK signaling in VSMC.
Life Sciences 04/2004; 74(17):2097-109. · 2.53 Impact Factor
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ABSTRACT: Two truncated forms of growth hormone (GH) receptor (GHR), 1-277 and 1-279, were reported to be normally produced in human tissues by alternative splicing in exon 9 and its boundary. We found previously that GHR-277 exerts a dominant-negative effect on full-length GHR (GHR-fl)-mediated GH signaling causing short stature. The existence of truncated GHRs (hGHR-tr) in normal tissues suggests that hGHR-tr may play a physiological role in regulation of GH action at the cellular level. To clarify the physiological significance of GHR-tr and the regulation mechanism of GHR-tr expression, we examined the expression of mouse GHR-tr (mGHR-tr) mRNA in mouse adipocyte 3T3-L1 cells, comparing with that of mouse GHR-fl (mGHR-fl). The mRNAs of two mGHR-tr, mGHR-282 and mGHR-280, were detected by RT-PCR methods using specific primers. Although the mGHR-282 and mGHR-280 mRNA levels were approximately 100 times lower than that of mGHR-fl in mature 3T3-L1 cells, quantitative analysis by competitive RT-PCR methods revealed that the mRNA levels of mGHR-280 in 3T3-L1 cells were transiently reduced and thereafter increased during differentiation from preadipocyte to adipocyte. In contrast, the mRNA levels of mGHR-fl were increased in parallel with the progress of differentiation. Stimulation by GH of differentiated 3T3-L1 mature adipocytes resulted in dose-dependent increases of the mRNA of both mGHR-fl and mGHR-282, whereas it caused a paradoxical decrease of the mRNA of mGHR-280 stimulated by high concentration of GH. These findings suggest that the expressions of truncated mGHRs were regulated in a different manner from that of mGHR-fl, thereby modulating GH action in murine adipocytes.
Molecular and Cellular Endocrinology 12/2003; 210(1-2):21-9. · 4.19 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 05/2003; 61 Suppl 4:80-5.
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ABSTRACT: Two truncated forms of growth hormone (GH) receptor (GHR), 1–277 and 1–279, were reported to be normally produced in human tissues by alternative splicing in exon 9 and its boundary. We found previously that GHR-277 exerts a dominant-negative effect on full-length GHR (GHR-fl)-mediated GH signaling causing short stature. The existence of truncated GHRs (hGHR-tr) in normal tissues suggests that hGHR-tr may play a physiological role in regulation of GH action at the cellular level. To clarify the physiological significance of GHR-tr and the regulation mechanism of GHR-tr expression, we examined the expression of mouse GHR-tr (mGHR-tr) mRNA in mouse adipocyte 3T3-L1 cells, comparing with that of mouse GHR-fl (mGHR-fl). The mRNAs of two mGHR-tr, mGHR-282 and mGHR-280, were detected by RT-PCR methods using specific primers. Although the mGHR-282 and mGHR-280 mRNA levels were approximately 100 times lower than that of mGHR-fl in mature 3T3-L1 cells, quantitative analysis by competitive RT-PCR methods revealed that the mRNA levels of mGHR-280 in 3T3-L1 cells were transiently reduced and thereafter increased during differentiation from preadipocyte to adipocyte. In contrast, the mRNA levels of mGHR-fl were increased in parallel with the progress of differentiation. Stimulation by GH of differentiated 3T3-L1 mature adipocytes resulted in dose-dependent increases of the mRNA of both mGHR-fl and mGHR-282, whereas it caused a paradoxical decrease of the mRNA of mGHR-280 stimulated by high concentration of GH. These findings suggest that the expressions of truncated mGHRs were regulated in a different manner from that of mGHR-fl, thereby modulating GH action in murine adipocytes.
Molecular and Cellular Endocrinology 210:21-29. · 4.19 Impact Factor
