State Key Laboratory of Freshwater Ecology and Biotechnology, Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Hubei Hongshan Laboratory, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
J Biol Chem. 2024 Jul;300(7):107405. doi: 10.1016/j.jbc.2024.107405. Epub 2024 May 22.
Exogenous omega-3 fatty acids, particularly docosahexaenoic acid (DHA), have shown to exert beneficial effects on nonalcoholic fatty liver disease (NAFLD), which is characterized by the excessive accumulation of lipids and chronic injury in the liver. However, the effect of endogenous DHA biosynthesis on the lipid homeostasis of liver is poorly understood. In this study, we used a DHA biosynthesis-deficient zebrafish model, elovl2 mutant, to explore the effect of endogenously biosynthesized DHA on hepatic lipid homeostasis. We found the pathways of lipogenesis and lipid uptake were strongly activated, while the pathways of lipid oxidation and lipid transport were inhibited in the liver of elovl2 mutants, leading to lipid droplet accumulation in the mutant hepatocytes and NAFLD. Furthermore, the elovl2 mutant hepatocytes exhibited disrupted mitochondrial structure and function, activated endoplasmic reticulum stress, and hepatic injury. We further unveiled that the hepatic cell death and injury was mainly mediated by ferroptosis, rather than apoptosis, in elovl2 mutants. Elevating DHA content in elovl2 mutants, either by the introduction of an omega-3 desaturase (fat1) transgene or by feeding with a DHA-rich diet, could strongly alleviate NAFLD features and ferroptosis-mediated hepatic injury. Together, our study elucidates the essential role of endogenous DHA biosynthesis in maintaining hepatic lipid homeostasis and liver health, highlighting that DHA deficiency can lead to NAFLD and ferroptosis-mediated hepatic injury.
外源性 ω-3 脂肪酸，特别是二十二碳六烯酸（DHA），已被证明对非酒精性脂肪性肝病（NAFLD）具有有益作用，其特征为肝脏内脂质过度积累和慢性损伤。然而，内源性 DHA 生物合成对肝脏脂质稳态的影响尚未被充分了解。在本研究中，我们使用 DHA 生物合成缺陷的斑马鱼模型，即 elovl2 突变体，来探索内源性生物合成的 DHA 对肝脏脂质稳态的影响。我们发现，elovl2 突变体肝脏中的脂肪生成和脂质摄取途径被强烈激活，而脂质氧化和脂质转运途径受到抑制，导致突变体肝细胞内脂质滴积累和 NAFLD。此外，elovl2 突变体肝细胞表现出线粒体结构和功能紊乱、内质网应激激活和肝损伤。我们进一步揭示，elovl2 突变体中的肝细胞死亡和损伤主要是由铁死亡介导的，而不是凋亡。在 elovl2 突变体中提高 DHA 含量，无论是通过引入 ω-3 去饱和酶（fat1）转基因还是通过富含 DHA 的饮食喂养，都能强烈缓解 NAFLD 特征和铁死亡介导的肝损伤。总之，本研究阐明了内源性 DHA 生物合成在维持肝脏脂质稳态和肝脏健康中的重要作用，强调了 DHA 缺乏可导致 NAFLD 和铁死亡介导的肝损伤。
