Inserm U954, Nutrition-Genetics-Environmental Risk Exposure (N-GERE), University of Lorraine, BP 184, 54511, Vandœuvre-lès-Nancy, France.
Sci Rep. 2016 Nov 17;6:37207. doi: 10.1038/srep37207.
Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet.
非酒精性脂肪性肝炎（NASH）是代谢综合征的一种表现形式，它是一个主要的公共卫生问题。在人类妊娠和哺乳期，甲基供体（叶酸和维生素 B12）缺乏很常见，会导致代谢综合征的胎儿编程效应，出生体重低，21 天大的（d21）幼鼠肝脏脂肪变性。我们研究了胎儿编程对来自缺乏母亲（iMDD）的幼鼠肝脏的影响，随后这些幼鼠在 d21 后接受正常饮食，在 d50 后接受高脂肪饮食（HF）。我们观察到 d50 iMDD 大鼠腹部脂肪增加，天冬氨酸氨基转移酶（ASAT）/丙氨酸氨基转移酶（ALAT）比值和血管紧张素水平升高，但肝脏组织学无异常。相比之下，d185 iMDD/HF 动物具有肝脂肪性肝炎的特征，炎症和纤维化标志物（caspase1、切割的白细胞介素 1β、α1(I)和α2(I)胶原和α-SMA）、胰岛素抵抗（HOMA-IR 和 Glut 2）以及参与肝星状细胞刺激和重塑以及触发 NASH 发病机制的关键基因（转化生长因子β超家族、血管紧张素和血管紧张素受体 1）的表达增加。我们的数据显示，MDD 对肝脏炎症和纤维化有胎儿编程效应，这表明需要研究妊娠期间 MDD 是否是人群在随后接触 HF 饮食后发生 NASH 的一个风险因素。
