脂肪变性
单酰甘油脂肪酶
医学
基因敲除
非酒精性脂肪肝
肝移植
促炎细胞因子
再灌注损伤
脂肪肝
内分泌学
肝损伤
内科学
脂肪性肝炎
移植
缺血
炎症
生物
细胞凋亡
生物化学
内大麻素系统
疾病
受体
作者
Kim Liss,Shelby Ek,Andrew J. Lutkewitte,Terri A. Pietka,Mai He,Priya Skaria,Eric Tycksen,Daniel Ferguson,Valérie Blanc,Mark Graham,A. Rupert Hall,Mitchell R. McGill,Kyle S. McCommis,Brian N. Finck
摘要
Nonalcoholic fatty liver disease (NAFLD) is becoming the most common indication for liver transplantation. The growing prevalence of NAFLD not only increases the demand for liver transplantation, but it also limits the supply of available organs because steatosis predisposes grafts to ischemia/reperfusion injury (IRI) and many steatotic grafts are discarded. We have shown that monoacylglycerol acyltransferase (MGAT) 1, an enzyme that converts monoacylglycerol to diacylglycerol, is highly induced in animal models and patients with NAFLD and is an important mediator in NAFLD-related insulin resistance. Herein, we sought to determine whether Mogat1 (the gene encoding MGAT1) knockdown in mice with hepatic steatosis would reduce liver injury and improve liver regeneration following experimental IRI. Antisense oligonucleotides (ASO) were used to knockdown the expression of Mogat1 in a mouse model of NAFLD. Mice then underwent surgery to induce IRI. We found that Mogat1 knockdown reduced hepatic triacylglycerol accumulation, but it unexpectedly exacerbated liver injury and mortality following experimental ischemia/reperfusion surgery in mice on a high-fat diet. The increased liver injury was associated with robust effects on the hepatic transcriptome following IRI including enhanced expression of proinflammatory cytokines and chemokines and suppression of enzymes involved in intermediary metabolism. These transcriptional changes were accompanied by increased signs of oxidative stress and an impaired regenerative response. We have shown that Mogat1 knockdown in a mouse model of NAFLD exacerbates IRI and inflammation and prolongs injury resolution, suggesting that Mogat1 may be necessary for liver regeneration following IRI and that targeting this metabolic enzyme will not be an effective treatment to reduce steatosis-associated graft dysfunction or failure.
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