Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.
Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease.
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DOI：
10.1002/hep.28953
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发表时间：
2017-04
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影响因子：
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通讯作者：
Griffin JL
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作者：
Hall Z;Bond NJ;Ashmore T;Sanders F;Ament Z;Wang X;Murray AJ;Bellafante E;Virtue S;Vidal-Puig A;Allison M;Davies SE;Koulman A;Vacca M;Griffin JL
非酒精性脂肪肝 (NAFLD) 可以从单纯性脂肪变性（即非酒精性脂肪肝 [NAFL]）进展为非酒精性脂肪性肝炎 (NASH)、肝硬化和癌症。目前，这一进展的驱动因素尚不完全清楚。特别是，目前尚不清楚 NAFLD 及其早期进展如何影响肝脏中脂质的分布，从而产生脂毒性和炎症。在这项研究中，我们使用了 NAFL 和 NASH 的饮食和遗传小鼠模型，并利用先进的质谱成像技术将肝组织中脂质的空间分布与疾病进展相关联，从而将结果转化为人类。我们在对照和 NAFL 样本中鉴定出了几种具有不同区域分布的脂质，并观察到 NASH 中脂质区域部分至完全丧失。此外，我们发现与磷脂膜重塑、膜中花生四烯酸（AA）释放以及促进炎症和细胞损伤的类二十烷酸物质产生相关的基因的肝脏表达增加。我们的免疫组织化学分析结果表明，重塑酶 LPCAT2 的区域位置在含 AA 脂质的空间分布变化中发挥作用。这导致了中央周围肝细胞中 AA 富集、AA 膜释放和促炎类花生酸生成的循环，并且可能是 NASH 中中央周围区域氧化损伤增加的原因。结论：NAFLD 不仅与脂质富集有关，还与特定脂质及其相关代谢途径的区域变化有关。这可能在 NAFLD 的异质性发展中发挥作用。 （肝病学 2017；65：1165‐1180）
Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)