Hepatocyte Deletion of Triglyceride-Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice
Hepatocyte Deletion of Triglyceride-Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice
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DOI：
10.1002/hep.30765
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发表时间：
2019-12-01
期刊：
影响因子：
13.5
通讯作者：
Walther, Tobias C.
中科院分区：
文献类型：
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作者：
Gluchowski, Nina L.;Gabriel, Katlyn R.;Walther, Tobias C.
非酒精性脂肪性肝病（NAFLD）的特征在于肝细胞中过量的脂质积聚，并且由于其发展为非酒精性脂肪性肝炎、纤维化和肝衰竭的倾向而代表巨大的公共卫生问题。储存在肝脂肪变性（HS）中的脂质主要是由两种酰基辅酶A：二酰基甘油酰基转移酶（DGAT）合成的甘油三酯（TG）。DGAT 1或DGAT 2催化该反应，并且已经表明这些酶分别有区别地利用外源或内源合成的脂肪酸。DGAT 2与从头脂肪生成的脂肪酸储存有关，这是一个在NAFLD中增加的过程。然而，DGAT 2是否对NAFLD中的脂质积累和向纤维化的进展更负责目前尚不清楚。此外，DGAT 2是否可以安全地抑制作为NAFLD的治疗方法还没有解决。在这里，我们通过喂养富含果糖、饱和脂肪和胆固醇的饮食诱导小鼠患NAFLD样疾病，发现肝细胞特异性Dgat2缺乏减少了从头脂肪生成基因的表达，并使肝脏TG降低了约70%。重要的是，脂肪变性的减少并不伴随着炎症或纤维化的增加，胰岛素和葡萄糖代谢没有改变。结论：这项研究表明，肝脏DGAT 2缺乏成功地减少了饮食诱导的HS，并支持DGAT 2抑制剂作为治疗NAFLD和预防下游后果的治疗策略的开发。
Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and represents a huge public health problem owing to its propensity to progress to nonalcoholic steatohepatitis, fibrosis, and liver failure. The lipids stored in hepatic steatosis (HS) are primarily triglycerides (TGs) synthesized by two acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, respectively. DGAT2 has been linked to storage of fatty acids from de novo lipogenesis, a process increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here, we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specific Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction in steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduces diet-induced HS and supports development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.