父母肥胖對后代非酒精性脂肪肝生成的影響
發(fā)布時間：2018-08-18 09:43
【摘要】：過去幾十年,兒童非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)的發(fā)病率在急劇增加,而這種患病率的快速增加并不單單是由兒童對高脂食物的過量攝取造成的。近來有關(guān)實驗動物的研究表明,對高脂食物喂養(yǎng)的肥胖母親的子代持續(xù)給予高脂食物喂養(yǎng),這些子代在成年后會比給予正常食物喂養(yǎng)的同窩子代更容易發(fā)生非酒精性脂肪肝炎。這表明：高脂食物喂養(yǎng)在一定條件下,可以通過代代傳遞的形式對代謝綜合癥的發(fā)生和發(fā)展產(chǎn)生擴大和加劇的作用。通過建立高脂食物連續(xù)喂養(yǎng)三代的母系肥胖小鼠模型,本論文作者對母系肥胖后代小鼠中NAFLD的產(chǎn)生進行了研究。另外,流行病學研究表明,肥胖及其相關(guān)疾病如NAFLD的發(fā)生過程中存在著性別差異。因此,論文作者進一步檢測了在持續(xù)母系營養(yǎng)過剩的條件下,后代小鼠中NAFLD的發(fā)生是否也存在性別差異。而且,父系肥胖也被證明對子代成年后疾病發(fā)生有一定影響,所以論文作者還建立了高脂食物連續(xù)喂養(yǎng)三代的父系肥胖小鼠模型來初步研究父系肥胖對其后代小鼠NAFLD產(chǎn)生的影響。 在母系肥胖和父系肥胖小鼠模型中,C57BL/6小鼠被分別用正常和高脂食物連續(xù)喂養(yǎng)三代：即FO代、F1代和F2代。論文作者對母系肥胖模型中后代小鼠的體重、食物攝取量、肝臟的組織學變化和血清中胰島素、瘦素、甘油三酯、肝臟功能指標和雌激素等水平、以及肝臟中甘油三酯含量水平進行了檢測；并且對其肝臟中脂肪生成、葡萄糖代謝、內(nèi)質(zhì)網(wǎng)應(yīng)激途徑相關(guān)因子的表達情況,細胞增殖和巨噬細胞標志物的蛋白水平以及組蛋白修飾狀態(tài)進行了研究。另外,父系肥胖雄鼠后代的體重、肝臟的組織學變化、肝臟中糖脂代謝通路相關(guān)基因的mRNA水平以及肝糖原的含量也都得到了檢測。 結(jié)果顯示：1)在持續(xù)高脂食物喂養(yǎng)條件下,隨著代數(shù)的增加,母系肥胖的雄鼠后代肥胖發(fā)生的時間更早且肥胖程度也更加嚴重,同時還伴隨著肝臟脂肪變性的逐漸加重(F2F1FO)。血清中的胰島素和瘦素水平也在持續(xù)高脂食物喂養(yǎng)的F2代雄鼠中最高。除此以外,脂肪生成和內(nèi)質(zhì)網(wǎng)應(yīng)激途徑也在這種母系肥胖模型的雄鼠后代中有著傳代積累的現(xiàn)象。而且,這兩個信號通路中的重要調(diào)控蛋白如LXRα(肝臟X受體α)和ERO1-α(內(nèi)質(zhì)網(wǎng)應(yīng)激氧化物蛋白1α)在這些雄鼠后代中呈現(xiàn)一定傳代性變化的趨勢,并伴隨著組蛋白甲基化水平和組蛋白H3K9雙甲基化水平的一定傳代性變化的趨勢。CHIP實驗也進一步表明,在持續(xù)高脂食物喂養(yǎng)的F2代雄鼠中,組蛋白的甲基化水平在LXRα和IERO1-α基因的啟動子區(qū)域上顯著下降。2)在持續(xù)高脂食物喂養(yǎng)條件下,母系肥胖的后代在肝臟脂肪變性過程中累積的信號通路存在性別差異。在連續(xù)的高脂食物喂養(yǎng)條件下,雖然肝臟病理變化以及血清中ALT和AST的水平在持續(xù)高脂食物喂養(yǎng)的F2代雄鼠和雌鼠之間是相似的,但是,雄鼠后代而并非雌鼠后代的肝臟中,細胞增殖和炎癥發(fā)生表現(xiàn)出傳代性積累；同時,雌鼠后代而并非雄鼠后代的肝臟中雌激素受體α的磷酸化水平表現(xiàn)出傳代性積累。3)在持續(xù)高脂食物喂養(yǎng)的父系肥胖條件下,2個月和4個月大的雄鼠后代的體重和肝臟重量等都沒有發(fā)生傳代性增加的變化；然而,在4個月大的雄鼠后代中,肝臟脂肪變性卻呈現(xiàn)出一定的傳代性惡化的現(xiàn)象。 因此,本論文的研究表明：在持續(xù)高脂食物喂養(yǎng)條件下,肥胖和NAFLD在母系肥胖的后代中都表現(xiàn)出傳代性加劇。而在雄鼠后代中,導致這種現(xiàn)象產(chǎn)生的原因可能是肝臟中組蛋白甲基化修飾的傳代性變化引起脂肪生成途徑和內(nèi)質(zhì)網(wǎng)應(yīng)激信號通路激活的傳代性積累。而且,母系肥胖的雄鼠后代和雌鼠后代中NAFLD的發(fā)生機制可能是不同的。細胞增殖和炎癥發(fā)生通路在雄鼠后代而并非在雌鼠后代中存在著傳代性積累,可能是為什么男性NAFLD患者更容易發(fā)展成惡性肝病的原因之一。另外,在較長時間的持續(xù)高脂食物喂養(yǎng)刺激下,父系肥胖對其雄鼠后代NAFLD的產(chǎn)生具有一定的傳代性影響,但這種影響的機制還需要進一步的研究。
[Abstract]:The incidence of nonalcoholic fatty liver disease (NAFLD) in children has increased dramatically in the past few decades, and this rapid increase is not solely due to children's excessive intake of high-fat foods. Recent studies in laboratory animals have shown that the offspring of obese mothers fed high-fat foods support this rapid increase. These offspring were more likely to develop non-alcoholic steatohepatitis in adulthood than the offspring fed normal food, suggesting that high-fat food feeding, under certain conditions, could play an expanding and intensifying role in the development of metabolic syndrome in the form of progeny transmission. In this paper, we studied the production of NAFLD in maternal obese offspring of mice fed with high-fat diet for three generations. In addition, epidemiological studies have shown that there are gender differences in the development of obesity and related diseases such as NAFLD. Therefore, the authors further examined the continuing maternal nutrition. In addition, paternal obesity has also been shown to have an effect on the development of disease in offspring, so the authors have established a paternal obesity mouse model fed with high-fat food for three generations to study the effect of paternal obesity on NAFLD in offspring. Ringing.
C57BL/6 mice were fed with normal and high-fat diets for three successive generations: FO, F1 and F2 in maternal obesity and paternal obesity mice, respectively. The levels of estrogen and triglyceride in the liver were measured, and the fatty production, glucose metabolism, the expression of endoplasmic reticulum stress pathway related factors, the levels of cell proliferation, macrophage markers and histone modification in the liver were studied. Generation weight, histological changes in the liver, mRNA levels of glycolipid metabolism pathway-related genes in the liver and glycogen content in the liver were also measured.
The results showed that: 1) With the increase of algebra, the offspring of maternal obese male rats were obese earlier and more severely, accompanied by progressive liver steatosis (F2F1FO). Serum insulin and leptin levels were also found in F2 male offspring fed continuously with high fat diet. In addition, adipogenesis and endoplasmic reticulum stress pathways also accumulated in the offspring of male mice with this maternal obesity model. Moreover, important regulatory proteins such as LXRalpha (liver X receptor alpha) and ERO1-alpha (endoplasmic reticulum stress oxide protein 1alpha) in these two signaling pathways exhibited certain transmission in these offspring of male mice. CHIP experiments also showed that histone methylation levels decreased significantly in the promoter regions of LXRalpha and IERO1-alpha genes in F2 male rats fed on high-fat diets. Sex differences in signal pathways accumulated during hepatic steatosis in maternal obese offspring fed on high-fat diets were observed. Proliferation and inflammation in the liver of offspring but not female mice showed passage accumulation; and phosphorylation of estrogen receptor alpha in the liver of offspring of female mice but not male mice showed passage accumulation. There was no change in body weight or liver weight, however, in the offspring of four-month-old male mice, liver steatosis showed a certain degree of deterioration.
Therefore, the present study suggests that obesity and NAFLD in maternal obese offspring increase in passage under continuous high-fat diet. In male offspring, this phenomenon may be due to histone methylation modification in the liver caused by the passage of fat production pathways and endoplasmic reticulum stress. The mechanism of NAFLD in maternal obese male offspring and female offspring may be different. Proliferation and inflammation pathways are present in male offspring, not in female offspring. This may be why male NAFLD patients are more likely to develop malignant liver disease. In addition, paternal obesity has a certain effect on the generation of NAFLD in male offspring, but the mechanism of this effect needs further study.
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R575.5
本文編號：2189085
[Abstract]:The incidence of nonalcoholic fatty liver disease (NAFLD) in children has increased dramatically in the past few decades, and this rapid increase is not solely due to children's excessive intake of high-fat foods. Recent studies in laboratory animals have shown that the offspring of obese mothers fed high-fat foods support this rapid increase. These offspring were more likely to develop non-alcoholic steatohepatitis in adulthood than the offspring fed normal food, suggesting that high-fat food feeding, under certain conditions, could play an expanding and intensifying role in the development of metabolic syndrome in the form of progeny transmission. In this paper, we studied the production of NAFLD in maternal obese offspring of mice fed with high-fat diet for three generations. In addition, epidemiological studies have shown that there are gender differences in the development of obesity and related diseases such as NAFLD. Therefore, the authors further examined the continuing maternal nutrition. In addition, paternal obesity has also been shown to have an effect on the development of disease in offspring, so the authors have established a paternal obesity mouse model fed with high-fat food for three generations to study the effect of paternal obesity on NAFLD in offspring. Ringing.
C57BL/6 mice were fed with normal and high-fat diets for three successive generations: FO, F1 and F2 in maternal obesity and paternal obesity mice, respectively. The levels of estrogen and triglyceride in the liver were measured, and the fatty production, glucose metabolism, the expression of endoplasmic reticulum stress pathway related factors, the levels of cell proliferation, macrophage markers and histone modification in the liver were studied. Generation weight, histological changes in the liver, mRNA levels of glycolipid metabolism pathway-related genes in the liver and glycogen content in the liver were also measured.
The results showed that: 1) With the increase of algebra, the offspring of maternal obese male rats were obese earlier and more severely, accompanied by progressive liver steatosis (F2F1FO). Serum insulin and leptin levels were also found in F2 male offspring fed continuously with high fat diet. In addition, adipogenesis and endoplasmic reticulum stress pathways also accumulated in the offspring of male mice with this maternal obesity model. Moreover, important regulatory proteins such as LXRalpha (liver X receptor alpha) and ERO1-alpha (endoplasmic reticulum stress oxide protein 1alpha) in these two signaling pathways exhibited certain transmission in these offspring of male mice. CHIP experiments also showed that histone methylation levels decreased significantly in the promoter regions of LXRalpha and IERO1-alpha genes in F2 male rats fed on high-fat diets. Sex differences in signal pathways accumulated during hepatic steatosis in maternal obese offspring fed on high-fat diets were observed. Proliferation and inflammation in the liver of offspring but not female mice showed passage accumulation; and phosphorylation of estrogen receptor alpha in the liver of offspring of female mice but not male mice showed passage accumulation. There was no change in body weight or liver weight, however, in the offspring of four-month-old male mice, liver steatosis showed a certain degree of deterioration.
Therefore, the present study suggests that obesity and NAFLD in maternal obese offspring increase in passage under continuous high-fat diet. In male offspring, this phenomenon may be due to histone methylation modification in the liver caused by the passage of fat production pathways and endoplasmic reticulum stress. The mechanism of NAFLD in maternal obese male offspring and female offspring may be different. Proliferation and inflammation pathways are present in male offspring, not in female offspring. This may be why male NAFLD patients are more likely to develop malignant liver disease. In addition, paternal obesity has a certain effect on the generation of NAFLD in male offspring, but the mechanism of this effect needs further study.
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R575.5
【參考文獻】
相關(guān)期刊論文 前2條
1 ;Prevalence and risk factors of fatty liver disease in Chengdu,Southwest China[J];Hepatobiliary & Pancreatic Diseases International;2009年04期
2 唐朝克,楊永宗;LXR和ABCA1對體內(nèi)膽固醇代謝的調(diào)節(jié)作用[J];生命的化學;2003年05期
，本文編號：2189085
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