摘要
研究表明,妊娠期母体营养不良导致后代出生重下降,影响机体葡萄糖的生成及线粒体的产能。线粒体在肝脏中数量丰富,提供细胞正常活动所需的ATP,其能量代谢水平易受营养水平的影响。妊娠期母体营养不良会降低后代肝脏胰岛素样生长因子的含量、促进脂肪在肝脏的沉积以及降低线粒体氧化磷酸化,这些研究大多以灵长类、啮齿类和反刍动物为研究对象,并且大多数研究关注成年期肝脏的变化,然而妊娠母猪营养不良对新生仔猪肝脏糖异生与线粒体功能的影响尚未见报道。新生动物肝脏糖异生与线粒体功能与机体代谢稳态和健康密切相关,本研究的目的是阐述妊娠母猪日粮蛋白水平对新生仔猪肝脏糖异生及线粒体功能的影响,并揭示其表遗传机制。
1母猪低蛋白日粮对新生仔猪肝脏糖异生的影响
14头初产纯种小梅山母猪随机分为标准蛋白组(SP,12%粗蛋白)和低蛋白组(LP,6%粗蛋白),饲养于江苏农林职业技术学院小梅山猪保种场。正式实验开始前进行一个月的预饲喂,使母猪适应低蛋白日粮,每天饲喂1.8kg饲料,分8：00和14：00两次饲喂。预饲喂期结束后,肌肉注射PG600同期发情并人工授精,妊娠母猪采取自然分娩,出生仔猪称重,测量体长、体高、胸围。母猪分娩结束后,立即从每窝新生仔猪中选取体重居中的雌性和雄性仔猪各1头,断头采集样品。
母猪低蛋白日粮显著降低了新生仔猪出生重(P<0.05)、肝重(P<0.01)、肾重(P<0.05)以及肾上腺重(P<0.05),同时,显著降低了新生仔猪血清葡萄糖(P<0.01)、乳酸(P<0.05)、赖氨酸(P<0.05)、苏氨酸(P<0.05)、异亮氨酸(P<0.05)和脯氨酸(P<0.05)的浓度。性别间比较发现,雄性仔猪体重(P<0.05)显著高于雌性仔猪,雄性仔猪血清中含有较高浓度的皮质醇(P=0.06),但未达到统计显著性。
母猪低蛋白日粮显著升高了新生仔猪肝糖原含量(P<0.05),并伴随着雄性新生仔猪肝脏葡萄糖-6-磷酸酶(G6PC)活性(P<0.05)的增加。用实时荧光定量PCR和Western blot方法检测肝脏糖异生相关基因和蛋白的表达,结果表明：母猪低蛋白日粮显著上调了雄性新生仔猪肝脏果糖-1,6-二磷酸酶(P<0.05)、G6PC (P<0.05)、过氧化物酶体增殖物激活受体丫辅激活因子lα(PGC-1α,P<0.05)与糖皮质激素受体(GR,P<0.05)的mRNA水平,同时,增加了细胞核内磷酸化GR (Ser211)蛋白的含量(P<0.05)。以上结果表明,母猪日粮蛋白水平影响了肝脏糖异生功能,并且存在性别差异。
2母猪低蛋白日粮对新生仔猪肝脏线粒体功能的影响
母猪低蛋白日粮显著升高了新生仔猪肝脏烟酰胺腺嘌呤二核苷酸(NADH)的浓度(P<0.05)以及NADH/NAD的值(P<0.05)。单磷酸腺苷(AMP)和能荷值都存在日粮(P<0.05)与性别(P<0.05)的互作效应,用最小显著性差异法比较发现,母猪低蛋白日粮显著升高雄性仔猪肝脏AMP的含量(P<0.05),能荷值有下降的趋势(P=0.06)；而雌性仔猪肝脏AMP (P<0.05)浓度显著降低,能荷值(P<0.05)显著上升。
另外,母猪低蛋白日粮显著增加了雄性仔猪肝脏细胞色素c氧化酶亚基Ⅰ (COX1, P<0.05)、细胞色素c氧化酶亚基Ⅱ (COX2, P<0.05)、细胞色素c氧化酶亚基Ⅲ (COX3, P<0.05)、烟酰胺腺嘌呤二核苷酸脱氢酶亚基Ⅲ(ND3,P<0.05)和细胞色素b基因(CYTB,P<0.05) mRNA水平,并提高了细胞色素c氧化酶(COX, P<0.05)的酶活性,而对LP组雌性仔猪肝脏线粒体DNA转录及COX酶活性都没有显著影响。这提示母猪低蛋白日粮对线粒体功能的改变也存在着性别特异性。
3母猪低蛋白日粮影响新生仔猪葡萄糖-6-磷酸酶及线粒体DNA转录调控的表遗传机制
首先,我们运用DNA步移法克隆得到了1213bp的G6PC基因5’端启动子序列,并用3’RACE技术克隆了960bp的G6PC基因3'UTR序列,然后运用甲基化DNA免疫共沉淀技术(MeDIP)、染色质免疫共沉淀技术(ChIP)分别对肝脏G6PC基因及线粒体DNA启动子区进行DNA甲基化、组蛋白修饰以及转录因子GR结合量的检测,同时还用实时荧光定量PCR检测了靶向G6PC3'UTR的miRNAs的表达。
母猪低蛋白日粮显著增加了雄性仔猪肝脏GR结合在G6PC外显子1(P<0.05)和启动子(P<0.05)的含量,同时也降低了雄性仔猪肝脏G6PC启动子的甲基化水平(P<0.05)；然而母猪低蛋白日粮显著增加了雌性仔猪肝脏GR结合在G6PC外显子1(P<0.05)的含量,但对G6PC启动子结合GR的含量以及DNA甲基化水平无显著影响。仔猪肝脏G6PC基因启动子组蛋白修饰也发现性别特异性：LP组雄性仔猪组蛋白H3(H3,P<0.05)和组蛋白H3K9三甲基化(H3K9me3, P<0.05)的富集程度较SP组显著降低,而组蛋白H3乙酰化(H3Ac, P<0.05)和组蛋白H3K4三甲基化(H3K4me3,P<0.05)的富集程度较SP组显著增加；LP组雌性仔猪则H3(P<0.05)的富集程度较SP组显著增加,而H3Ac (P<0.05)和H3K9、K4三甲基化(P<0.05)的富集程度较SP组均显著增加,另外,靶向G6PC基因3’UTR的ssc-miR-339-5p (P<0.05)和ssc-miR-532-3p (P<0.05)的表达上调。
从母猪日粮蛋白水平对线粒体DNA启动子甲基化程度的研究来看,母体低蛋白日粮显著降低了雄性新生仔猪肝脏线粒体DNA启动子区5’-甲基胞嘧啶(P<0.01)和5’-羟甲基胞嘧啶(P<0.05)的甲基化水平,然而显著升高了雌性新生仔猪肝脏ntDNA启动子5’-甲基胞嘧啶(P<0.01)和5’-羟甲基胞嘧啶(P<0.01)甲基化水平。
综上所述,以上结果提示母体低蛋白情况下,糖皮质激素通过GR调控新生仔猪肝脏能量代谢,并且表遗传机制参与了对G6PC和线粒体DNA的转录调控。
Epidemiological and animal studies indicate that maternal malnutrition during pregnancy results in low birthweight and impacts body's energy metabolism. The liver is rich in mitochondria, which are involved in generating most of the cell's supply of ATP for normal functions. The level of energy metabolism is vulnerable to nutritional insults. Maternal malnutrition during pregnancy reduces the content of hepatic insulin-like growth factor, promotes fat deposition and impairs mitochondrial oxidative phosphorylation in the liver of offsprings. While most of these studies use primates, rodents and goats as model, and mainly focus on adult animals, no reports are available on the effect of malnutrition in pregnant sows on hepatic gluconeogenesis and mitochondrial function in newborn piglets. Hepatic gluconeogenesis and mitochondrial function are of particular importance in neonates for energy homeostasis and health. Therefore, the purpose of this study was to describe the effect of sows feeding low protein diet on hepatic gluconeogenesis and mitochondrial function in newborn piglets and its underlying epigenetic mechanisms.
1Effects of maternal low protein diet during pregnancy on hepatic gluconeogenesis in newborn piglets
The animal experiment was conducted in the National Meishan Pig Preservation and Breeding Farm at Jiangsu Polytechnic College of Agriculture and Forestry, Jurong, Jiangsu Province, P. R. China. Fourteen primiparous purebred Meishan gilts (body weight:36.1±1.8kg) were assigned randomly into standard (SP) and low (LP) protein groups. The SP sows were fed on diets containing12%crude protein during gestation, while those in LP group were fed diets containing6%crude protein. The dietary treatment began one month before artificial insemination at the first observation of estrus. Sows were fed twice daily (0800and1400h) with the rations of1.8kg/day during gestation. After the pre-feeding, estrus synchronization was conducted by intramuscular injection of PG600. The birthweight, length, height and bust of the piglets were documented after birth. One male and one female piglet of the mean body weight (±10%) were selected from each litter and exsanguinated before sucking, and samples were collected.
Maternal LP diet during pregnancy significantly reduced the birth weight (P<0.05), liver weight (P<0.01), kidney weight (P<0.05) and adrenal weight (P<0.05) in male newborn piglets. In addition, maternal LP diet significantly reduced the concentrations of serum glucose (P<0.01), lactic acid (P<0.05), lysine (P<0.05), threonine (P<0.05), isoleucine (P<0.05), and proline (P <0.05). Comparing between genders, the birth weight (P<0.05) and the serum cortisol concentration (P=0.06) in males was significantly or tended to be higher than in females.
Maternal LP diet significantly increased hepatic glycogen content in LP piglets (P<0.05), associated with enhanced liver G6PC enzyme activity (P<0.05). Realtime PCR and Western blot were performed to detect gene and protein expression. Maternal LP diet significantly increased hepatic FBP1(P<0.05), G6PC (P<0.01), PGC-la (P<0.05) and GR (P<0.05) gene expression in males. In addition, the nuclear p-Ser211GR (P<0.05) protein content was significant enhanced in LP male newborns. These results indicate that maternal LP diet impacts hepactic gluconeogenesis in a gender-specific manner.
2Effects of maternal low protein diet during pregnancy on hepatic mitochondrial function in newborn piglets
Maternal LP diet significantly increased the concentration of hepatic NADH (P<0.05) and the ratio of NADH/NAD (P<0.05). Hepatic AMP concentration and energy charge were effected significantly by diet x sex interaction. Maternal LP diet significantly increased the concentration of hepatic AMP (P<0.05) and significantly decreased energy charge (P<0.05) in male newborns, while the opposite was observed in female newborns.
In addition, maternal LP diet significantly increased hepatic COX1(P<0.05), COX2(P<0.05), COX3(P<0.05), ND3(P<0.05) and CYTB (P<0.05) gene expression, which was accompied by significantly increased enzyme activity of COX (P<0.05) in males but not in females. These results indicate that maternal LP diet exerts a gender dependent effect on mitochondrial function in newborn piglets.
3Epigenetic mechanisms underlying the effect of maternal low protein diet on transcriptional regulation of hepatic G6PC and mitochondrial coding genes
First, we cloned1213bp promoter sequence of G6PC by genomic DNA walking. Moreover,960bp3'UTR sequence of G6PC was cloned by RACE. Then the methods of MedIP and ChIP were used to detect DNA methylation, histone modification and GR binding.
Maternal LP diet significantly increased GR binding to G6PC promoter and exon1in both males (P<0.05) and females (P<0.05), yet the methylation level of G6PC (P<0.01) promoter was significantly decreased only in male piglets, but not female. Also, we found gender difference in histone modifications in newborn piglets. In male newborns, maternal LP diet significantly reduced the enrichment of H3(P<0.01) on the promoter of G6PC gene in liver, increased the enrichment of H3Ac (P<0.05) and H3K4me3(P<0.05) and decreased the enrichment of H3K9me3(P<0.05) on the promoter of G6PC gene. In females, the enrichment of H3(P<0.05), H3K4me3(P<0.01), H3K9me3(P<0.05) and H3K27me3(P<0.05) were all significantly increased in the LP group. Moreover, maternal LP significantly reduced the expression level of ssc-miR-339-5p (P<0.05) and ssc-miR-532-3p (P<0.01), which target at the3'UTR of G6PC, in females.
Maternal low protein diet significantly decreased the methylation of5mc (P<0.01) and5hmc (P <0.05) in hepatic mitochondrial DNA promoter in male piglets while decreased the methylation of5mc (P<0.01) and5hmc (P<0.05) in hepatic mitochondrial DNA promoter in female piglets. These results indicate that the effects of maternal low protein diet on hepatic energy metabolism in newborn piglets are mediated through GR and epigenetic mechanisms involved in transcriptional regulation of G6PC and mitochondrial coding genes.
引文
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