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

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 (PPARα) 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, PPARα expression, and ferroptosis were examined in the cellular NAFLD model. Additionally, the effects of FMO1 and/or PPARα 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 in vitro NAFLD model. FMO1 knockdown suppressed the FFA-induced accumulation of lipids in hepatocytes, downregulation of PPARα expression, and upregulation of ferroptosis. In contrast, FMO1 overexpression dysregulated lipid metabolism and downregulated PPARα levels. Meanwhile, PPARα overexpression mitigated the FMO1 overexpression-induced upregulation of ferroptosis and lipid accumulation. Treatment with RSL3 suppressed the effects of PPARα overexpression on lipid accumulation and FMO1 expression.

CONCLUSIONS:

FMO1 upregulates ferroptosis by suppressing PPARα in NAFLD, which leads to the dysregulation of lipid metabolism.

• Authors: Lin Zou, Qin Shi, Yingxuan Li, Zhen Yuan, Li Peng, Jiancan Lu, Hongling Zhu, Junhua Ma
• Journal: Discovery medicine (Discov Med) Vol. 35 Issue 177 Pg. 612-622 (08 2023) ISSN: 1944-7930 [Electronic] United States
• PMID: 37553313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Author(s). Published by Discovery Medicine.

Chemical References

• PPAR alpha
• dimethylaniline monooxygenase (N-oxide forming)
• Fatty Acids, Nonesterified

Topics

• Humans
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• PPAR alpha (genetics, metabolism, pharmacology)
• Ferroptosis
• Fatty Acids, Nonesterified
• Lipid Metabolism (genetics)
• Liver (metabolism)