Gutierrez Sanchez Luz Helena, Tomita Kyoko, Guo Qianqian, Furuta Kunimaro, Alhuwaish Husam, Hirsova Petra, Baheti Saurabh, Alver Bonnie, Hlady Ryan, Robertson Keith D, Ibrahim Samar H
Division of Pediatric Gastroenterology and Hepatology Mayo Clinic Rochester MN.
Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN.
Hepatol Commun. 2018 Oct 1;2(12):1493-1512. doi: 10.1002/hep4.1265. eCollection 2018 Dec.
With the epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The influence of a perinatal obesity-inducing diet (OID) on the development and progression of NAFLD in offspring is important but incompletely studied. Hence, we fed breeding pairs of C57BL/6J mice during gestation and lactation (perinatally) either chow or an OID rich in fat, fructose, and cholesterol (FFC). The offspring were weaned to either chow or an FFC diet, generating four groups: perinatal (p)Chow-Chow, pChow-FFC, pFFC-Chow, and pFFC-FFC. Mice were sacrificed at 10 weeks of age. We examined the whole-liver transcriptome by RNA sequencing (RNA-seq) and whole-liver genome methylation by reduced representation bisulfite sequencing (RRBS). Our results indicated that the pFFC-FFC mice had a significant increase in hepatic steatosis, injury, inflammation, and fibrosis, as assessed histologically and biochemically. We identified 189 genes that were differentially expressed and methylated in the pFFC-FFC mice versus the pChow-FFC mice. Gene set enrichment analysis identified hepatic fibrosis/hepatic stellate cell activation as the top canonical pathway, suggesting that the differential DNA methylation events in the mice exposed to the FFC diet perinatally were associated with a profibrogenic transcriptome. To verify that this finding was consistent with perinatal nutritional reprogramming of the methylome, we exposed pFFC-Chow mice to an FFC diet in adulthood. These mice developed significant hepatic steatosis, injury, inflammation, and more importantly fibrosis when compared to the appropriate controls. : Perinatal exposure to an OID primes the immature liver for an accentuated fibrosing nonalcoholic steatohepatitis (NASH) phenotype, likely through nutritional reprogramming of the offspring methylome. These data have potential clinical implications for monitoring children of obese mothers and risk stratification of children with NAFLD.
随着肥胖症的流行，非酒精性脂肪性肝病（NAFLD）已成为最常见的儿科肝脏疾病。围产期致肥胖饮食（OID）对后代NAFLD发生发展的影响很重要，但尚未得到充分研究。因此，我们在妊娠和哺乳期（围产期）给C57BL/6J小鼠繁殖对喂食普通饲料或富含脂肪、果糖和胆固醇（FFC）的OID。将后代断奶后分别喂食普通饲料或FFC饲料，分为四组：围产期（p）普通饲料-普通饲料组、p普通饲料-FFC组、pFFC-普通饲料组和pFFC-FFC组。在10周龄时处死小鼠。我们通过RNA测序（RNA-seq）检测全肝转录组，并通过简化代表性亚硫酸氢盐测序（RRBS）检测全肝基因组甲基化。我们的结果表明，从组织学和生化角度评估，pFFC-FFC小鼠的肝脂肪变性、损伤、炎症和纤维化显著增加。我们鉴定出189个在pFFC-FFC小鼠与p普通饲料-FFC小鼠中差异表达和甲基化的基因。基因集富集分析确定肝纤维化/肝星状细胞激活为首要的经典通路，表明围产期暴露于FFC饮食的小鼠中差异DNA甲基化事件与促纤维化转录组相关。为了验证这一发现与甲基化组的围产期营养重编程一致，我们在成年期将pFFC-普通饲料组小鼠暴露于FFC饮食。与适当的对照组相比，这些小鼠出现了显著的肝脂肪变性、损伤、炎症，更重要的是纤维化。结论：围产期暴露于OID可能通过后代甲基化组的营养重编程，使未成熟肝脏更容易出现加重的纤维化非酒精性脂肪性肝炎（NASH）表型。这些数据对监测肥胖母亲的子女以及对NAFLD儿童进行风险分层具有潜在的临床意义。
