孕鼠高膽固醇血症對小鼠子代非酒精性脂肪肝及代謝疾病發展之影響

隨著飲食趨向西化以及代謝疾病的高盛行率，尋找疾病形成原因加以預防越發重要。目前認為早期發育為關鍵調控時期，因此我們欲探討孕期前後以西方飲食誘導母體血脂異常是否加速子代代謝疾病發展，並深入研究其機制。我們以 ApoE-/- 小鼠為模式，妊娠前分別以控制或西方飲食誘導母鼠高膽固醇血症，延續至仔鼠離乳後統一餵食控制飲食。仔鼠分為親代控制飲食-子代控制飲食 (CC) 與親代西方飲食-子代控制飲食 (WC) 兩組。 16 週齡子代雄性 WC 與 CC 相比出現非酒精性脂肪肝及葡萄糖不耐症，18.5 天胚胎肝臟基因表現中，發現母鼠以西方飲食餵食的胚胎肝臟 de novo lipogenesis (DNL) 相關基因會被上調，加速肝臟脂質堆積。另外，成鼠血液脂蛋白譜分析觀察到 WC 子代雄性與 CC 子代雄性相比有較少極低密度脂蛋白 (VLDL) 的趨勢，探討其機制，發現血清中與 VLDL 組裝相關的 ApoB 含量較低，肝臟ApoB 基因表現也顯著較 CC 低，進一步發現 ApoB DNA 甲基化程度在 WC 組較 CC 高。最後，我們發現 WC 子代雄性與 CC 子代雄性相比葡萄糖耐受性較差，性腺脂肪在胰島素刺激後 AKT 磷酸化程度也較低，顯示胰島素訊息傳導受阻。由我們實驗結果證實，母親高膽固醇血症可能會透過 DNA 甲基化方式影響子代肝臟基因表現，或胰島素訊息傳導，進而促使非酒精性脂肪肝與葡萄糖不耐症形成。

關鍵字

母體效應；高膽固醇血症；非酒精性脂肪肝；胰島素阻抗；表觀遺傳

並列摘要

There is increasing evidence that early developmental environment of an embryo plays a pivotal role in the ‘programming’ of an adverse physiological phenotype in later life. Here we sought for the influence of maternal hyperlipidemia on the metabolic disorders in offspring. In our study, ApoE knockout females were fed with either control or western diet during pregnancy and lactation to induce hyperlipidemia. All offspring were fed with control diet starting from weaning to 16-week of age. Two experimental groups were generated: CC group (maternal/postnatal control diet), and WC group (maternal western diet/postnatal control diet). We monitored body weight and serum lipid levels every month, performing glucose and insulin tolerance test at 14/15-week of age. Our data show that WC group had impaired insulin sensitivity and hepatic lipid accumulation in adult offspring when compared to CC group. We found the hepatic de novo lipogenesis pathway (DNL pathway) was upregulated in the E18.5 embryo exposured to maternal western diet; but had adverse results in adult offspring. In additionl, we investigated that the VLDL secretion reduced from liver and ApoB, which is required for VLDL component, mRNA expression was decreased in WC group; there had similar appearance in E18.5 embryo. Moreover, in the WC group, a higher percentage of ApoB DNA methylation was observed in liver compared with CC group. Here, we demonstrate that exposure to hyperlipidemia during early developmental period will sensitize the offspring to induction of Nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes mellitus; furthermore, the DNA methylation might the key epigenetic regulatory mechanisms, providing a potential therapeutic targets in NAFLD.