Ghrelin对奶山羊泌乳调节作用研究
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摘要
Ghrelin是从大鼠胃中分离纯化得到的含有28氨基酸残基的活性肽，参与摄食、生长激素（growth hormone，GH）分泌、能量平衡、免疫、生殖和泌乳等多种生理功能的调节，有关Ghrelin对泌乳调控的研究资料较少，且大部分都是从鼠上获得的。本文以奶山羊为研究对象，通过检测Ghrelin和GHSR-1a在奶山羊体内的表达分布和各泌乳相关激素在泌乳周期变化规律，确定Ghrelin对奶山羊泌乳的调节作用，检测Ghrelin对离体乳腺组织和乳腺上皮细胞功能影响，进一步确定Ghrelin对乳腺泌乳活动的调节作用。研究取得如下结果。
1. Ghrelin及其受体GHSR-1a mRNA在成年奶山羊消化道、下丘脑、垂体、卵巢和乳腺组织中均有表达，在消化道，皱胃Ghrelin mRNA和蛋白表达量最高，Ghrelin和GHSR-1a阳性细胞在整个消化道都有分布，在皱胃，Ghrelin阳性细胞大体可分为开放和闭锁两种类型，在肠道，Ghrelin阳性细胞大部分分布于肠腺上皮之间，而在食道、瘤胃和网胃中，Ghrelin阳性细胞多为复层鳞状上皮的基底细胞。GHSR-1a阳性细胞多分布于消化道的神经节细胞、平滑肌细胞和腺细胞之间。结果表明，Ghrelin可能通过乳腺组织中的GHSR-1a直接调控乳腺组织的泌乳活动，也可能通过对摄食、能量平衡和生殖的调节间接地调控反刍动物泌乳活动。
2.在泌乳期奶山羊皱胃中均可检测到Ghrelin mRNA和蛋白的表达，在乳腺组织中也可检测到Ghrelin及其受体GHSR-1a mRNA和蛋白的表达，Ghrelin和GHSR-1a主要表达于乳腺导管及乳腺上皮细胞中。泌乳期奶山羊皱胃Ghrelin变化与乳腺组织中β-casein变化趋势一致，乳腺组织中Ghrelin和β-casein的变化趋势一致，从泌乳前期到泌乳下降期，奶山羊乳腺组织中GHSR-1a的变化与β-casein变化趋势一致。结果表明，Ghrelin可能通过内分泌、旁分泌和自分泌方式调控乳腺组织的泌乳活动。
3.在泌乳期奶山羊皱胃Ghrelin及垂体中Ghrelin、GHSR-1a和GH的表达量变化趋势与泌乳量的变化趋势基本一致。泌乳初期，垂体Ghrelin、GHSR-1a和GH表达量相对较低，而泌乳高峰期，grhelin、GHSR-1a和GH的表达量均达到峰值，随后逐渐降低。下丘脑促生长激素释放激素（growth hormone releasing hormone，GHRH）和生长激素释放抑制激素（somatostatin，SST）的表达量变化与垂体GH表达量的变化并不完全一致，泌乳初期，GHRH和SST的表达量均处于最低水平，泌乳高峰期，GHRH水平达到峰值，同时SST的水平较泌乳初期显著升高，泌乳下降期和干奶期，GHRH水平呈现先降后升再降低的趋势，而SST水平则呈现先升后降再升高的趋势，而垂体中GH表达量一直呈现平稳下降趋势。结果显示，Ghrelin和GHSR-1a变化与GH和泌乳量的变化密切相关，提示Ghrelin与GHRH和SST相互协调、共同调控GH的分泌释放，进而调节反刍动物的泌乳活动。
4. Ghrelin可以促进离体乳腺组织分泌β-casein，且呈现出一定的时间和剂量依赖性。Ghrelin在10~3pg/mL时对离体乳腺组织分泌β-casein促进作用最强，当浓度提高到104、105pg/mL时，Ghrelin对乳腺组织分泌β-casein的促进作用减弱。以10~3pg/mL Ghrelin处理乳腺组织18h后，Ghrelin上调乳腺组织分泌β-casein的作用最强，处理24h、30h后，Ghrelin促进乳腺组织分泌β-casein减弱。D-Lys3-GHRP-6可明显抑制Ghrelin上调乳腺组织分泌β-casein作用，且这种抑制作用具有剂量依赖性。
5. Ghrelin可以促进原代乳腺上皮细胞中β-casein的分泌，这种促进作用具有一定的时间和剂量依赖性。10~3pg/mL Ghrelin上调乳腺上皮细胞分泌β-casein的作用最强，当浓度提高到104、105pg/mL时，Ghrelin促进原代乳腺上皮细胞分泌β-casein作用减弱，以10~3pg/mL的浓度处理原代乳腺上皮细胞18h后，Ghrelin对原代乳腺上皮细胞分泌β-casein的促进作用最强，处理24h、30h后，Ghrelin促进原代乳腺上皮细胞分泌β-casein作用减弱，尤其是处理30h后，与对照组相比，Ghrelin的促进作用无显著性差异。抑制剂D-Lys3-GHRP-6可以显著抑制Ghrelin上调原代乳腺上皮细胞分泌β-casein的作用，且呈剂量依赖性。Ghrelin可以促进原代乳腺上皮细胞的增殖，其中10~3pg/mL Ghrelin促进作用最强。而105pg/mL Ghrelin对原代乳腺上皮细胞的增殖具有一定的抑制作用，但与对照组相比差异不显著。
本研究阐明了Ghrelin及其受体GHSR-1a在奶山羊分布及变化规律，揭示了Ghrelin及其受体GHSR-1a和泌乳相关激素与奶山羊泌乳的关系，检测了Ghrelin对离体乳腺组织和乳腺上皮细胞泌乳功能的影响，为进一步研究Ghrelin调节泌乳的分子机制提供理论依据。
Ghrelin, isolated and purified from the rat stomach, is active peptide containing28amino acid residues, and involved in regulating many physiological function such as feeding,GH secretion, energy balance, immune, reproductive and lactation, the data about the effect ofGhrelin on regulating lactation are very few and mostly from rats. In this study, the dairy goatwas the research object. through detecting distribution of Ghrelin and GHSR-1a in dairy goatand the change of hormones related to lactation during lactating period, determine the effectof Ghrelin on regulating lactation of dairy goat, and then through the detection of effect ofGhrelin on the function of mammary tissue and mammary epithelial cells, further todetermine the role of Ghrelin in regulating lactating activity of mammary tissue, The resultswere as follows:
1. Ghrelin and its functional receptor GHSR-1a mRNA expressed in the digestive tract,hypothalamus, pituitary, ovary and mammary tissue of dairy goat. In the digestive tract, theGhrelin mRNA and protein expression level was highest in the abomasum. Ghrelin and itsreceptor GHSR-1a positive cells could be detected in the digestive tract, and the Ghrelinpositive cells could be divided into two types: open and closed type. In the intestine, Ghrelinpositive cells located mostly in the intestinal gland epithelium cells, in the esophage, rumenand reticulum, Ghrelin positive cells were basal cells of stratified squamous epithelia, inmammary tissue, Ghrelin positive cells mostly were ductal and acinar epithelial cells.GHSR-1a distributed in the ganglion cells, smooth muscle cells, gland cells of digestive tractand ductal and acinar epithelial cells of mammary tissue. The results show that Ghrelin canregulat lactation by GHSR-1a in the mammary tissue directly，and also regulate lactation byregulating food intake, energy balance and reproduction of the ruminants indirectly.
2. Ghrelin mRNA and protein could be detected in the dairy goat abomasum, and Ghrelinand its receptor GHSR-1a mRNA and protein could be also detect in the dairy goat mammarytissue during lactation, Ghrelin and GHSR-1a mainly expressed in mammary duct andmammary epithelial cells. The change trend of Ghrelin in the abomasum was in agreementwith that of β–CS in the mammary tissue. From early lactation to lactation decline period, threvariation trend of GHSR-1a was agreement with that of β-casein in the mammary tissue, it indicates that Ghrelin may regulate lactating via endocrine, paracrine and autocrine manners.
3. The expression change of Ghrelin in abomasums, Ghrelin, GHSR-1a and GH inpituitary were consistent with that of milk production during lactation. Early lactation, theexpression of Ghrelin, GHSR-1a and GH expression was relatively low in pituitary, at thepeak of lactation, the expression of Ghrelin, GHSR-1a and GH reached the peak, thengradually decreased. The expression change of growth hormone releasing hormone (GHRH)and somatostatin (SST) were not adjusted to that of GH completely. Early lactation, Theexpression of GHRH and SST were at the lowest level, at the peak of lactation, GHRH levelreached the peak, at the same time the SST level was significantly increased compared withthat in early lactation, decline and dry period, The GHRH level showed the trend ofincrease-decrease-increase, and the SST level showed the trend of decrease-increase-decrease,while the level of GH showed steady downward trend. Results show that changes of Ghrelinand GHSR-1a levels are closely related to changes of amount of lactation, suggesting thatGhrelin can regulate GH secretion interacting with GHRH and SST, and affect lactating ofruminant animals at the hypothalamus and pituitary levels.
4. Ghrelin could promote mammary tissue secreting β-casein in vitro, and in a certainrange, this effect of Ghrelin showed time and dose dependence. The effect of10~3pg/mLGhrelin to promote mammary tissue secreting β-casein in vitro was strongest, when theconcentration was increased to104,105pg/mL, The effect of Ghrelin became weakly. Treatedmammry tissue with10~3pg/mL Ghrelin for18h, the effect to promote mammary tissuesecreting β-casein strongest, When the treatment time was24h,30h, the effect of Ghrelindecreased. D-Lys3-GHRP6can inhibit Ghrelin effect on mammary tissue, and this inhibitoryeffect showed dose dependent.
5. Ghrelin could promote induce the primary mammary epithelial cells secreting β-casein,and in a certain range, this effect of Ghrelin had time and dose dependence.10~3pg/mLGhrelin had the highest effect to promote primary mammary epithelial cells secreting β-casein,when the concentration was increased to104,105pg/mL, The effect of Ghrelin becameweakly.Treated primary mammary epithelial cells with10~3pg/mL Ghrelin for18h, the effectto promote mammary tissue secreting β-casein strongest, When the treatment time was24h,30h, the effect of Ghrelin decreased. Inhibitor D-Lys3-GHRP6could inhibit the effect ofGhrelin to up-regulating mammary epithelial cells secreting β-casein, and this inhibitingeffect showed dose dependence. Ghrelin can promote the proliferation of primary mammaryepithelial cell, and the effect of10~3pg/mL Ghrelin to promote the proliferation of mammaryepithelial cells was strongest, while the105pg/mL Ghrelin on proliferation of primarymammary epithelial cells have a certain inhibitory effect, but compared with the control group, the difference was not significant.
This paper expounded the variation of Ghrelin and its receptor GHSR-1a in dairy goatduring lactation, and revealed the relationship between Ghrelin and its receptor GHSR-1a andother related hormones of dairy goat during lactation in vivo, detected the effect of Ghrelin onmammary tissue and epithelial cell in vitro, and provided the theory basis for furtherresearching molecular mechanism of Ghrelin role during lactation.
1. Ghrelin及其受体GHSR-1a mRNA在成年奶山羊消化道、下丘脑、垂体、卵巢和乳腺组织中均有表达，在消化道，皱胃Ghrelin mRNA和蛋白表达量最高，Ghrelin和GHSR-1a阳性细胞在整个消化道都有分布，在皱胃，Ghrelin阳性细胞大体可分为开放和闭锁两种类型，在肠道，Ghrelin阳性细胞大部分分布于肠腺上皮之间，而在食道、瘤胃和网胃中，Ghrelin阳性细胞多为复层鳞状上皮的基底细胞。GHSR-1a阳性细胞多分布于消化道的神经节细胞、平滑肌细胞和腺细胞之间。结果表明，Ghrelin可能通过乳腺组织中的GHSR-1a直接调控乳腺组织的泌乳活动，也可能通过对摄食、能量平衡和生殖的调节间接地调控反刍动物泌乳活动。
2.在泌乳期奶山羊皱胃中均可检测到Ghrelin mRNA和蛋白的表达，在乳腺组织中也可检测到Ghrelin及其受体GHSR-1a mRNA和蛋白的表达，Ghrelin和GHSR-1a主要表达于乳腺导管及乳腺上皮细胞中。泌乳期奶山羊皱胃Ghrelin变化与乳腺组织中β-casein变化趋势一致，乳腺组织中Ghrelin和β-casein的变化趋势一致，从泌乳前期到泌乳下降期，奶山羊乳腺组织中GHSR-1a的变化与β-casein变化趋势一致。结果表明，Ghrelin可能通过内分泌、旁分泌和自分泌方式调控乳腺组织的泌乳活动。
3.在泌乳期奶山羊皱胃Ghrelin及垂体中Ghrelin、GHSR-1a和GH的表达量变化趋势与泌乳量的变化趋势基本一致。泌乳初期，垂体Ghrelin、GHSR-1a和GH表达量相对较低，而泌乳高峰期，grhelin、GHSR-1a和GH的表达量均达到峰值，随后逐渐降低。下丘脑促生长激素释放激素（growth hormone releasing hormone，GHRH）和生长激素释放抑制激素（somatostatin，SST）的表达量变化与垂体GH表达量的变化并不完全一致，泌乳初期，GHRH和SST的表达量均处于最低水平，泌乳高峰期，GHRH水平达到峰值，同时SST的水平较泌乳初期显著升高，泌乳下降期和干奶期，GHRH水平呈现先降后升再降低的趋势，而SST水平则呈现先升后降再升高的趋势，而垂体中GH表达量一直呈现平稳下降趋势。结果显示，Ghrelin和GHSR-1a变化与GH和泌乳量的变化密切相关，提示Ghrelin与GHRH和SST相互协调、共同调控GH的分泌释放，进而调节反刍动物的泌乳活动。
4. Ghrelin可以促进离体乳腺组织分泌β-casein，且呈现出一定的时间和剂量依赖性。Ghrelin在10~3pg/mL时对离体乳腺组织分泌β-casein促进作用最强，当浓度提高到104、105pg/mL时，Ghrelin对乳腺组织分泌β-casein的促进作用减弱。以10~3pg/mL Ghrelin处理乳腺组织18h后，Ghrelin上调乳腺组织分泌β-casein的作用最强，处理24h、30h后，Ghrelin促进乳腺组织分泌β-casein减弱。D-Lys3-GHRP-6可明显抑制Ghrelin上调乳腺组织分泌β-casein作用，且这种抑制作用具有剂量依赖性。
5. Ghrelin可以促进原代乳腺上皮细胞中β-casein的分泌，这种促进作用具有一定的时间和剂量依赖性。10~3pg/mL Ghrelin上调乳腺上皮细胞分泌β-casein的作用最强，当浓度提高到104、105pg/mL时，Ghrelin促进原代乳腺上皮细胞分泌β-casein作用减弱，以10~3pg/mL的浓度处理原代乳腺上皮细胞18h后，Ghrelin对原代乳腺上皮细胞分泌β-casein的促进作用最强，处理24h、30h后，Ghrelin促进原代乳腺上皮细胞分泌β-casein作用减弱，尤其是处理30h后，与对照组相比，Ghrelin的促进作用无显著性差异。抑制剂D-Lys3-GHRP-6可以显著抑制Ghrelin上调原代乳腺上皮细胞分泌β-casein的作用，且呈剂量依赖性。Ghrelin可以促进原代乳腺上皮细胞的增殖，其中10~3pg/mL Ghrelin促进作用最强。而105pg/mL Ghrelin对原代乳腺上皮细胞的增殖具有一定的抑制作用，但与对照组相比差异不显著。
本研究阐明了Ghrelin及其受体GHSR-1a在奶山羊分布及变化规律，揭示了Ghrelin及其受体GHSR-1a和泌乳相关激素与奶山羊泌乳的关系，检测了Ghrelin对离体乳腺组织和乳腺上皮细胞泌乳功能的影响，为进一步研究Ghrelin调节泌乳的分子机制提供理论依据。
Ghrelin, isolated and purified from the rat stomach, is active peptide containing28amino acid residues, and involved in regulating many physiological function such as feeding,GH secretion, energy balance, immune, reproductive and lactation, the data about the effect ofGhrelin on regulating lactation are very few and mostly from rats. In this study, the dairy goatwas the research object. through detecting distribution of Ghrelin and GHSR-1a in dairy goatand the change of hormones related to lactation during lactating period, determine the effectof Ghrelin on regulating lactation of dairy goat, and then through the detection of effect ofGhrelin on the function of mammary tissue and mammary epithelial cells, further todetermine the role of Ghrelin in regulating lactating activity of mammary tissue, The resultswere as follows:
1. Ghrelin and its functional receptor GHSR-1a mRNA expressed in the digestive tract,hypothalamus, pituitary, ovary and mammary tissue of dairy goat. In the digestive tract, theGhrelin mRNA and protein expression level was highest in the abomasum. Ghrelin and itsreceptor GHSR-1a positive cells could be detected in the digestive tract, and the Ghrelinpositive cells could be divided into two types: open and closed type. In the intestine, Ghrelinpositive cells located mostly in the intestinal gland epithelium cells, in the esophage, rumenand reticulum, Ghrelin positive cells were basal cells of stratified squamous epithelia, inmammary tissue, Ghrelin positive cells mostly were ductal and acinar epithelial cells.GHSR-1a distributed in the ganglion cells, smooth muscle cells, gland cells of digestive tractand ductal and acinar epithelial cells of mammary tissue. The results show that Ghrelin canregulat lactation by GHSR-1a in the mammary tissue directly，and also regulate lactation byregulating food intake, energy balance and reproduction of the ruminants indirectly.
2. Ghrelin mRNA and protein could be detected in the dairy goat abomasum, and Ghrelinand its receptor GHSR-1a mRNA and protein could be also detect in the dairy goat mammarytissue during lactation, Ghrelin and GHSR-1a mainly expressed in mammary duct andmammary epithelial cells. The change trend of Ghrelin in the abomasum was in agreementwith that of β–CS in the mammary tissue. From early lactation to lactation decline period, threvariation trend of GHSR-1a was agreement with that of β-casein in the mammary tissue, it indicates that Ghrelin may regulate lactating via endocrine, paracrine and autocrine manners.
3. The expression change of Ghrelin in abomasums, Ghrelin, GHSR-1a and GH inpituitary were consistent with that of milk production during lactation. Early lactation, theexpression of Ghrelin, GHSR-1a and GH expression was relatively low in pituitary, at thepeak of lactation, the expression of Ghrelin, GHSR-1a and GH reached the peak, thengradually decreased. The expression change of growth hormone releasing hormone (GHRH)and somatostatin (SST) were not adjusted to that of GH completely. Early lactation, Theexpression of GHRH and SST were at the lowest level, at the peak of lactation, GHRH levelreached the peak, at the same time the SST level was significantly increased compared withthat in early lactation, decline and dry period, The GHRH level showed the trend ofincrease-decrease-increase, and the SST level showed the trend of decrease-increase-decrease,while the level of GH showed steady downward trend. Results show that changes of Ghrelinand GHSR-1a levels are closely related to changes of amount of lactation, suggesting thatGhrelin can regulate GH secretion interacting with GHRH and SST, and affect lactating ofruminant animals at the hypothalamus and pituitary levels.
4. Ghrelin could promote mammary tissue secreting β-casein in vitro, and in a certainrange, this effect of Ghrelin showed time and dose dependence. The effect of10~3pg/mLGhrelin to promote mammary tissue secreting β-casein in vitro was strongest, when theconcentration was increased to104,105pg/mL, The effect of Ghrelin became weakly. Treatedmammry tissue with10~3pg/mL Ghrelin for18h, the effect to promote mammary tissuesecreting β-casein strongest, When the treatment time was24h,30h, the effect of Ghrelindecreased. D-Lys3-GHRP6can inhibit Ghrelin effect on mammary tissue, and this inhibitoryeffect showed dose dependent.
5. Ghrelin could promote induce the primary mammary epithelial cells secreting β-casein,and in a certain range, this effect of Ghrelin had time and dose dependence.10~3pg/mLGhrelin had the highest effect to promote primary mammary epithelial cells secreting β-casein,when the concentration was increased to104,105pg/mL, The effect of Ghrelin becameweakly.Treated primary mammary epithelial cells with10~3pg/mL Ghrelin for18h, the effectto promote mammary tissue secreting β-casein strongest, When the treatment time was24h,30h, the effect of Ghrelin decreased. Inhibitor D-Lys3-GHRP6could inhibit the effect ofGhrelin to up-regulating mammary epithelial cells secreting β-casein, and this inhibitingeffect showed dose dependence. Ghrelin can promote the proliferation of primary mammaryepithelial cell, and the effect of10~3pg/mL Ghrelin to promote the proliferation of mammaryepithelial cells was strongest, while the105pg/mL Ghrelin on proliferation of primarymammary epithelial cells have a certain inhibitory effect, but compared with the control group, the difference was not significant.
This paper expounded the variation of Ghrelin and its receptor GHSR-1a in dairy goatduring lactation, and revealed the relationship between Ghrelin and its receptor GHSR-1a andother related hormones of dairy goat during lactation in vivo, detected the effect of Ghrelin onmammary tissue and epithelial cell in vitro, and provided the theory basis for furtherresearching molecular mechanism of Ghrelin role during lactation.
引文
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