Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor
Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor
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DOI：
10.1530/joe-13-0055
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Hardy, Daniel B.
中科院分区：
文献类型：
--
作者：
Vo, ThinXuan;Revesz, Andrew;Hardy, Daniel B.
流行病学研究表明，出生后追赶生长加剧了胎儿发育受损和晚年糖耐量不耐受之间的联系。孕期和哺乳期的母体蛋白质限制(MPR)可导致成年后的糖耐量受损，但在断奶期间蛋白质恢复对葡萄糖稳态的影响尚不清楚。最近的体外研究发现，肝X受体α(LXRα)通过抑制G6pase(G6pc)、11β-HSD1(Hsd11b1)和PEPCK(Pck 1)等参与糖异生的关键基因来维持血糖的动态平衡。因此，我们假设MPR在出生后追赶生长会损害体内的LXRα，这反过来会导致糖异生LXRα靶基因表达增强和葡萄糖耐量降低。为了验证这一假设，怀孕的Wistar大鼠在怀孕期间被喂以对照(20%)蛋白质饮食(C)或低蛋白质饮食(8%)，并在出生时切换到对照饮食(LP)。在4个月时，LP后代的葡萄糖耐量受损。此外，LP子代降低了LXRα的表达，而肝脏11β-HSD1和G6Pase的表达显著升高。这伴随着LXRα与11β-HSD1和G6pase上可能的LXRE结合减少。最后，我们证明了组蛋白H3(K9，14)在肝LXRα转录起始点(Nr1H3)周围的乙酰化水平在LP后代中降低，这表明MPR诱导LXRα启动子的表观遗传沉默。综上所述，我们的研究首次证明了LXRα在介导成年MPR后代肝脏糖异生基因表达增强和继而导致的葡萄糖耐量增加中的重要作用。
Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the liver X receptor alpha (LXR alpha) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11 beta-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXR alpha in vivo, which in turn would lead to augmented gluconeogenic LXR alpha-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXR alpha expression, while hepatic expression of 11 beta-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXR alpha to the putative LXRE on 11 beta-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic LXR alpha (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the LXR alpha promoter. In summary, our study demonstrates for the first time the important role of LXR alpha in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring.