FMO1 通过调节 PPARα 激活和诱导铁死亡促进非酒精性脂肪性肝病进展。
FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis.
机构信息
Department of Endocrinology, Gongli Hospital of Shanghai Pudong New Area, 200135 Shanghai, China.
Department of General Practice, Gongli Hospital of Shanghai Pudong New Area, 200135 Shanghai, China.
出版信息
Discov Med. 2023 Aug;35(177):612-622. doi: 10.24976/Discov.Med.202335177.60.
BACKGROUND
The function of flavin containing dimethylaniline monooxygenase 1 (FMO1), which is known to play a part in lipid metabolism, remains unclear in the development of nonalcoholic fatty liver disease (NAFLD). This research has the objective of examining the contributions of FMO1 in the progression of NAFLD and the associated mechanisms, particularly the peroxisome proliferator activated receptor alpha (PPARα) and ferroptosis pathways.
METHODS
An NAFLD model was established by treating L02 cells with free fatty acids (FFAs). The FMO1 and ferroptosis levels were examined in the cellular NAFLD model. was knocked down using short-interfering RNA transfection. The effects of knockdown on lipid accumulation, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of and/or overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARα agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs.
RESULTS
The levels of FMO1 and ferroptosis were upregulated in the NAFLD model. knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, overexpression mitigated the overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of overexpression on lipid accumulation and FMO1 expression.
CONCLUSIONS
FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.
背景
黄素单加氧酶 1（FMO1）的功能，已知其在脂质代谢中发挥作用，但在非酒精性脂肪性肝病（NAFLD）的发展中仍不清楚。本研究旨在研究 FMO1 在 NAFLD 进展中的作用及其相关机制，特别是过氧化物酶体增殖物激活受体α（PPARα）和铁死亡途径。
方法
用游离脂肪酸（FFAs）处理 L02 细胞建立 NAFLD 模型。检测细胞 NAFLD 模型中 FMO1 和铁死亡水平。用短发夹 RNA 转染敲低 。在细胞 NAFLD 模型中检测 敲低对脂质积累、PPARα表达和铁死亡的影响。此外，还分析了 和/或 过表达对脂质代谢和铁死亡的影响。此外，用 GW7647（PPARα激动剂）或 RSL3（铁死亡激活剂）预处理 L02 细胞，然后用 FFAs 刺激。
结果
在 NAFLD 模型中，FMO1 和铁死亡水平上调。 敲低抑制了 FFA 诱导的肝细胞脂质积累、PPARα表达下调和铁死亡上调。相反， 过表达扰乱了脂质代谢并下调了 PPARα 水平。同时， 过表达减轻了 过表达诱导的铁死亡和脂质积累上调。用 RSL3 处理抑制了 过表达对脂质积累和 FMO1 表达的影响。
结论
FMO1 通过抑制 NAFLD 中的 PPARα 上调铁死亡，导致脂质代谢失调。
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