Triglyceride peroxidation progression in lipid droplets of hepatocytes in nonalcoholic steatohepatitis
Triglyceride peroxidation progression in lipid droplets of hepatocytes in nonalcoholic steatohepatitis
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DOI：
10.1530/rem-22-0024
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发表时间：
2023-01
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影响因子：
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通讯作者：
K. Saito;Y. Matsuoka;M. Abe;Nao Kato;Kazushi Morimoto;Ken‐ichi Yamada
中科院分区：
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作者：
K. Saito;Y. Matsuoka;M. Abe;Nao Kato;Kazushi Morimoto;Ken‐ichi Yamada
非酒精性脂肪性肝炎是一种由单纯性脂肪变性引起的肝细胞死亡和炎症进展引起的慢性肝脏疾病。然而，该病的发病机制尚不清楚。脂质过氧化是非酒精性脂肪性肝炎发生的关键因素之一；然而，氧化脂质-脂质过氧化的产物-分析不足。在这里，我们全面分析了胆碱缺乏、l-氨基酸定义、高脂肪饮食喂养的小鼠模型中非酒精性脂肪性肝炎发展过程中的肝脏氧化脂质。收集C57BL/6J小鼠的肝脏，分别饲喂标准饮食或缺乏胆碱的l-氨基酸高脂肪饮食1、3或6周，以评估纤维化、脂肪变性、炎症、肝损伤和氧化脂质产生，并观察维生素E对这些参数的抑制作用。此外，使用荧光成像评估脂质过氧化的细胞器定位。最后，给模型小鼠注射线粒体靶向抗氧化剂，以研究脂质过氧化的机制。我们发现在非酒精性脂肪性肝炎的早期阶段氧化甘油三酯积累。此外，我们的数据表明氧化甘油三酯是由线粒体衍生的活性氧在脂滴中的脂质过氧化作用产生的。这些结果提示脂滴过氧化在非酒精性脂肪性肝炎进展中的重要性，并可能有助于未来非酒精性脂肪性肝炎治疗方法的发展。我们证明了非酒精性脂肪性肝炎发病机制中脂质过氧化的特异性和早期发生，并提出了一种以前未知的疾病进展机制。
Nonalcoholic steatohepatitis is a chronic liver disease caused by the progression of hepatocellular death and inflammation from simple steatosis. However, the pathogenesis of this disease remains unclear. Lipid peroxidation is one of the most critical factors in the development of nonalcoholic steatohepatitis; however, oxidised lipids – the products of lipid peroxidation – are insufficiently analysed. Here, we comprehensively analysed oxidised lipids in the liver during nonalcoholic steatohepatitis development in a choline-deficient, l-amino acid-defined, high-fat diet-fed mouse model. Liver from C57BL/6J mice, fed a standard diet or a choline-deficient l-amino acid-defined high-fat diet for 1, 3, or 6 weeks, were collected to evaluate fibrosis, steatosis, inflammation, liver injury, and oxidised lipid production and to observe the suppression of these parameters upon vitamin E administration. In addition, organellar localisation of lipid peroxidation was assessed using fluorescence imaging. Finally, a mitochondria-targeted antioxidant was administered to model mice to investigate the mechanism underlying lipid peroxidation. We found an accumulation of oxidised triglycerides in the early stages of nonalcoholic steatohepatitis. Furthermore, our data indicate that oxidised triglycerides are generated by lipid peroxidation in lipid droplets due to mitochondria-derived reactive oxygen species. These results suggest the importance of lipid droplet peroxidation in the progression of nonalcoholic steatohepatitis and may contribute to the development of therapeutic methods for nonalcoholic steatohepatitis in the future. We demonstrate the specific and early occurrence of lipid peroxidation in nonalcoholic steatohepatitis pathogenesis and propose a previously unknown mechanism of disease progression.