Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity.
Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity.
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DOI：
10.3389/fcell.2022.830009
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发表时间：
2022
影响因子：
5.5
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中科院分区：
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近几十年来，肥胖已经成为一个公共卫生问题，在怀孕期间，它可能会导致妊娠并发症的风险增加，并通过一种称为代谢编程的过程导致后代发生永久性变化。肥胖母鸡的后代患非酒精性脂肪肝(NAFLD)的风险增加，即使在没有高脂饮食的情况下也是如此。非酒精性脂肪性肝病是一种慢性脂肪性肝病，可发展到极其严重的情况，需要手术切除受损组织。肝脏再生是保护器官功能所必需的。在肝再生过程中，一系列信号通路被激活，包括受表观遗传控制的河马、转化生长因子β和AMPK信号通路。我们研究了肥胖大鼠后代肝脏中的microRNA调节是否会影响HIPPO、转化生长因子β和AMPK通路的基因表达以及肝部分切除后的组织再生。雌性瑞士小鼠在怀孕和哺乳前和期间喂食标准食物或高脂饮食(HFD)，与雄性对照组小鼠交配。对照组(CT-O)和肥胖组(HF-O)的后代断奶至56d接受PHX手术。如前所述，在手术前，与CT-O相比，HF-O在肝脏中的miR-122、miR-370和let-7a的表达以及参与肝脏再生的靶基因发生了变化。然而，在PHX(术后4小时或48小时)后，CT-O和HF-O之间的基因表达差异以及肝脏microRNA表达的差异被抑制。此外，CT-O和HF-O在PHX后48小时内表现出相似的肝脏再生能力。我们的结果表明，肝部分切除诱导的存活和再生机制可能克服了母体肥胖导致的子代肝脏的表观遗传学变化。
Obesity has become a public health problem in recent decades, and during pregnancy, it can lead to an increased risk of gestational complications and permanent changes in the offspring resulting from a process known as metabolic programming. The offspring of obese dams are at increased risk of developing non-alcoholic fatty liver disease (NAFLD), even in the absence of high-fat diet consumption. NAFLD is a chronic fatty liver disease that can progress to extremely severe conditions that require surgical intervention with the removal of the injured tissue. Liver regeneration is necessary to preserve organ function. A range of pathways is activated in the liver regeneration process, including the Hippo, TGFβ, and AMPK signaling pathways that are under epigenetic control. We investigated whether microRNA modulation in the liver of the offspring of obese dams would impact gene expression of Hippo, TGFβ, and AMPK pathways and tissue regeneration after partial hepatectomy (PHx). Female Swiss mice fed a standard chow or a high-fat diet (HFD) before and during pregnancy and lactation were mated with male control mice. The offspring from control (CT-O) and obese (HF-O) dams weaned to standard chow diet until day 56 were submitted to PHx surgery. Prior to the surgery, HF-O presented alterations in miR-122, miR-370, and Let-7a expression in the liver compared to CT-O, as previously shown, as well as in its target genes involved in liver regeneration. However, after the PHx (4 h or 48 h post-surgery), differences in gene expression between CT-O and HF-O were suppressed, as well as in microRNA expression in the liver. Furthermore, both CT-O and HF-O presented a similar regenerative capacity of the liver within 48 h after PHx. Our results suggest that survival and regenerative mechanisms induced by the partial hepatectomy may overcome the epigenetic changes in the liver of offspring programmed by maternal obesity.