Non-alcoholic fatty liver disease-associated DNA methylation and gene expression alterations in the livers of Collaborative Cross mice fed an obesogenic high-fat and high-sucrose diet.
Non-alcoholic fatty liver disease-associated DNA methylation and gene expression alterations in the livers of Collaborative Cross mice fed an obesogenic high-fat and high-sucrose diet.
复制标题
喂食导致肥胖的高脂肪和高蔗糖饮食的 Collaborative Cross 小鼠肝脏中与非酒精性脂肪肝相关的 DNA 甲基化和基因表达改变。
DOI：
10.1080/15592294.2022.2043590
复制
发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Pogribny,IgorP
中科院分区：
文献类型：
--
作者：
Tryndyak,VolodymyrP;Willett,RoseA;Avigan,MarkI;Sanyal,ArunJ;Beland,FrederickA;Rusyn,Ivan;Pogribny,IgorP
非酒精性脂肪性肝病（NAFLD）是一种高度流行的慢性肝病，患者对其发病和进展的易感性受到多种因素的影响。在这项研究中，我们研究了肝组织中改变的肝DNA甲基化是否与协作杂交（CC）小鼠中高脂肪和高蔗糖（HF/HS）饮食诱导的NAFLD样肝损伤的严重程度相关。使用全基因组靶向亚硫酸氢盐DNA甲基化下一代测序，我们发现具有不同非酒精性脂肪肝（NAFL）表型的小鼠可以通过肝脏DNA甲基化谱的变化来区分。具体而言，NAFL倾向的雄性CC 042小鼠与雄性CC 011小鼠和雌性CC 011和CC 042小鼠相比表现出更显著的DNA甲基化变化，后者仅表现出轻度NAFL表型。此外，这些小鼠品系表现出不同的DNA甲基化模式。虽然HF/HS饮食在所有小鼠品系中诱导DNA低甲基化和DNA高甲基化变化，但NAFL倾向的雄性CC 042小鼠表现出DNA高甲基化的全球优势，而在轻度NAFL表型小鼠中出现更明显的DNA低甲基化模式。在对含有差异甲基化区域（DMR）的选定基因的靶向分析中，我们确定了严重NAFL易感小鼠中与NAFL表型相关的DNA甲基化和Apoa 4、Gls 2和Apom基因表达的差异，但在轻度NAFL表型小鼠中没有。Apoa 4和Gls 2表达的这些变化与饮食诱导的脂肪变性体外细胞模型和NAFL患者中的类似结果一致。这些结果表明，这三个基因的表达和DNA甲基化状态的变化可以作为一组预测NAFLD发生的标志物。
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease, and patient susceptibility to its onset and progression is influenced by several factors. In this study, we investigated whether altered hepatic DNA methylation in liver tissue correlates with the degree of severity of NAFLD-like liver injury induced by a high-fat and high-sucrose (HF/HS) diet in Collaborative Cross (CC) mice. Using genome-wide targeted bisulphite DNA methylation next-generation sequencing, we found that mice with different non-alcoholic fatty liver (NAFL) phenotypes could be distinguished by changes in hepatic DNA methylation profiles. Specifically, NAFL-prone male CC042 mice exhibited more prominent DNA methylation changes compared with male CC011 mice and female CC011 and CC042 mice that developed only a mild NAFL phenotype. Moreover, these mouse strains demonstrated different patterns of DNA methylation. While the HF/HS diet induced both DNA hypomethylation and DNA hypermethylation changes in all the mouse strains, the NAFL-prone male CC042 mice demonstrated a global predominance of DNA hypermethylation, whereas a more pronounced DNA hypomethylation pattern developed in the mild-NAFL phenotypic mice. In a targeted analysis of selected genes that contain differentially methylated regions (DMRs), we identified NAFL phenotype-associated differences in DNA methylation and gene expression of theApoa4, Gls2, andApomgenes in severe NAFL-prone mice but not in mice with mild NAFL phenotypes. These changes in the expression ofApoa4andGls2coincided with similar findings in a human in vitro cell model of diet-induced steatosis and in patients with NAFL. These results suggest that changes in the expression and DNA methylation status of these three genes may serve as a set of predictive markers for the development of NAFLD.