發(fā)布時間：2018-10-13 15:20

【摘要】：哺乳動物的生長發(fā)育由一系列復(fù)雜的神經(jīng)內(nèi)分泌免疫調(diào)節(jié)系統(tǒng)調(diào)控，它起源于下丘腦。而下丘腦分泌兩種對于腦垂體細(xì)胞很重要的肽類：促生長激素釋放激素GHRH和生長抑素SST。GHRH作用于腦垂體促進(jìn)生長激素GH的分泌，從而增加肝臟和其他組織中胰島素樣生長因子類IGF-1的生成，而GH在肝臟以IGF-1的形式促進(jìn)機(jī)體新陳代謝。 BHBA作為一種重要的脂肪酸代謝的中間代謝物，它的作用類似于葡萄糖，能夠?yàn)榇竽X提供能量，尤其是新生嬰兒。近年來，研究顯示BHBA在下丘腦中能夠調(diào)節(jié)激素的合成和分泌。然而，BHBA介導(dǎo)激素調(diào)節(jié)或者BHBA調(diào)節(jié)CHRH的合成和分泌機(jī)制的報道比較少。研究顯示，BHBA能夠通過GPR109A受體抑制LPS誘導(dǎo)的炎癥。另有研究顯示，BHBA能夠通過GPR109A受體促進(jìn)脂連素的分泌。 本課題組在前期的研究中發(fā)現(xiàn)，在離體培養(yǎng)的下丘腦神經(jīng)細(xì)胞中有BHBA的受體GPR109A的表達(dá)。因此，我們假設(shè)BHBA通過GPR109A及其下游信號調(diào)控GHRH的合成分泌。在我們的實(shí)驗(yàn)研究中，大鼠體內(nèi)實(shí)驗(yàn)顯示BHBA使GHRH基因轉(zhuǎn)錄顯著下調(diào)。體外實(shí)驗(yàn)顯示，BHBA處理離體培養(yǎng)的下丘腦神經(jīng)細(xì)胞后GHRH的合成和分泌減少，但是當(dāng)PTX預(yù)處理后，這種效應(yīng)被抑制。在GT1-7細(xì)胞系中，，BHBA對GHRH的合成和分泌無明顯作用。而在含有GPR109A受體的GT1-7細(xì)胞系中，BHBA對GHRH的合成和分泌明顯抑制，且這一效應(yīng)可被PTX阻斷。此外，BHBA能顯著下調(diào)同源基因Gsh-1轉(zhuǎn)錄水平，同樣PTX也能阻斷這種效應(yīng)。蛋白免疫印跡結(jié)果顯示，離體培養(yǎng)的下丘腦神經(jīng)細(xì)胞中BHBA能激活ERK1/2，p38和JNK MAPK信號通路。且ERK1/2信號通路抑制劑U0126能減弱BHBA抑制Gsh-1表達(dá)、GHRH合成分泌的效應(yīng)。這些結(jié)果提示，BHBA通過GPR109A/ERK1/2MAPK通路能下調(diào)Gsh-1的表達(dá)和GHRH的合成分泌。
[Abstract]:Mammalian growth and development are regulated by a series of complex neuroendocrine and immunomodulatory systems, which originate from the hypothalamus. However, hypothalamus secretes two kinds of peptides that are important to pituitary cells: growth hormone releasing hormone (GHRH) and somatostatin (SST.GHRH), which promote the secretion of growth hormone (GH) in pituitary gland. Thus increasing the production of insulin-like growth factor-like IGF-1 in liver and other tissues, while GH promotes the metabolism of the body in the form of IGF-1 in the liver. BHBA is an important intermediate metabolite of fatty acid metabolism. It acts like glucose and provides energy to the brain, especially newborn babies. In recent years, studies have shown that BHBA regulates hormone synthesis and secretion in the hypothalamus. However, there are few reports of BHBA mediating hormone regulation or BHBA regulating the synthesis and secretion of CHRH. Studies have shown that BHBA can inhibit LPS-induced inflammation through GPR109A receptors. Other studies have shown that BHBA promotes adiponectin secretion through GPR109A receptors. In our previous study, we found the expression of BHBA receptor GPR109A in cultured hypothalamic neurons. Therefore, we assume that BHBA regulates the synthesis and secretion of GHRH through GPR109A and its downstream signals. In our study, in vivo experiments in rats showed that BHBA significantly down-regulated the transcription of GHRH gene. In vitro experiments showed that the synthesis and secretion of GHRH decreased after BHBA treatment of cultured hypothalamic nerve cells, but this effect was inhibited after pretreatment with PTX. In GT1-7 cell line, BHBA has no effect on the synthesis and secretion of GHRH. In GT1-7 cell line containing GPR109A receptor, BHBA significantly inhibited the synthesis and secretion of GHRH, and this effect could be blocked by PTX. In addition, BHBA significantly down-regulated the transcription level of homologous gene Gsh-1, and PTX also blocked this effect. Western blot showed that BHBA could activate ERK1/2,p38 and JNK MAPK signaling pathway in cultured hypothalamic neurons. ERK1/2 signaling pathway inhibitor U0126 can attenuate the inhibitory effect of BHBA on Gsh-1 expression and GHRH synthesis and secretion. These results suggest that BHBA can down-regulate the expression of Gsh-1 and the synthesis and secretion of GHRH through GPR109A/ERK1/2MAPK pathway.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：S852.21

【共引文獻(xiàn)】

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