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FMO1 Promotes Nonalcoholic Fatty Liver Disease Progression by Regulating PPARα Activation and Inducing Ferroptosis

Lin Zou,Qin Shi, Yingxuan Li, Zhen Yuan,Li Peng,Jiancan Lu,Hongling Zhu,Junhua Ma

DISCOVERY MEDICINE(2023)

Cited 2|Views9
Abstract
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 (PPARa) and ferroptosis pathways.Methods: An in vitro 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. FMO1 was knocked down using short-interfering RNA transfection. The effects of FMO1 knockdown on lipid accumulation, PPARa expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of FMO1 and/or PPARa overexpression on lipid metabolism and ferroptosis were analyzed. Furthermore, L02 cells were pre-treated with GW7647 (PPARa agonist) or RSL3 (ferroptosis activator) and stimulated with FFAs.Results: The levels of FMO1 and ferroptosis were upregulated in the in vitro NAFLD model. FMO1 knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARa expression, and upregulation of ferroptosis. In contrast, FMO1 overexpression dysregulated lipid metabolism and downregulated PPARa levels. Meanwhile, PPARa overexpression mitigated the FMO1 overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of PPARa overexpression on lipid accumulation and FMO1 expression.Conclusions: FMO1 upregulates ferroptosis by suppressing PPARa in NAFLD, which leads to the dysregulation of lipid metabolism.
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Key words
nonalcoholic fatty liver disease,FMO1,PPAR & alpha,ferroptosis,lipid metabolism
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