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Published on: April 26, 2019
Bisphenol AF Induces Hepatic Steatosis via Succinate-SUCNR1-Mediated Macrophage-Hepatocyte Interactions: An Adverse
Ning Wang1, Jing Leng1, Huimin Zhang1
1Shanghai Municipal Center for Disease Control and Prevention, Institute of Chemical Safety Evaluation/Key Laboratory of Environmental and Health Impact Assessment of New Pollutants, 1399 at Shenhong Road, Shanghai 201107, China.
Abstract:
Bisphenol AF (BPAF) exposure is increasingly linked to metabolic disorders, yet the molecular initiating events (MIE) and key events (KE) leading to hepatic steatosis remain unclear. We constructed an adverse outcome pathway (AOP) to mechanistically connect BPAF-triggered macrophage-hepatocyte crosstalk to liver fat accumulation. Male C57BL/6 mice received daily oral gavage of 0, 0.5, 4, or 32 mg kg-1 BPAF for 90 d, and Transwell co-cultures of RAW264.7 macrophages and AML12 hepatocytes were used for in vitro validation. Targeted metabolomics, western blotting, and lipid staining quantified succinate, pathway proteins, and steatosis. BPAF dose-dependently increased serum succinate (BMD = 6901.95 nM) and hepatic triglyceride (TG) (BMD = 874.26 nM). Cryo-EM docking revealed BPAF binding to SUCNR1 at 2.9 Å, disrupting the inactive-state conformation. In co-culture, BPAF-exposed macrophages released succinate that bound hepatocyte SUCNR1, suppressed Akt phosphorylation, and activated JNK. These KEs led to a 40% increase in lipid droplets and elevated TG, total cholesterol (TC), and free fatty acids (FFA) without liver weight gain. We propose the first AOP for BPAF-induced hepatic steatosis: BPAF-SUCNR1 binding (MIE) → macrophage succinate release (KE1) → SUCNR1-mediated Akt inhibition/JNK activation (KE2-4) → hepatic lipid accumulation (KE5) → steatosis (AO). These findings provide mechanistic insight for chemical risk assessment of BPAF and structurally related bisphenols.
Insights
Bisphenol AF (BPAF) causes liver fat accumulation by disrupting macrophage-hepatocyte communication. This study details the adverse outcome pathway (AOP) linking BPAF exposure to hepatic steatosis via succinate signaling.
Area of Science:
- Environmental Toxicology
- Metabolic Disorders
- Molecular Toxicology
Background:
- Bisphenol AF (BPAF) exposure is associated with metabolic disorders.
- The molecular mechanisms driving BPAF-induced hepatic steatosis are not fully understood.
- Understanding the crosstalk between macrophages and hepatocytes is crucial for elucidating liver fat accumulation.
Purpose of the Study:
- To construct an adverse outcome pathway (AOP) for BPAF-induced hepatic steatosis.
- To investigate the molecular initiating events (MIE) and key events (KE) connecting BPAF exposure to liver fat accumulation.
- To elucidate the role of macrophage-hepatocyte crosstalk in BPAF-mediated steatosis.
Main Methods:
- In vivo study using male C57BL/6 mice exposed to varying doses of BPAF for 90 days.
- In vitro validation using Transwell co-cultures of RAW264.7 macrophages and AML12 hepatocytes.
- Quantification of succinate, pathway proteins, and hepatic steatosis using targeted metabolomics, western blotting, and lipid staining.
- Cryo-electron microscopy (Cryo-EM) docking to assess BPAF binding to SUCNR1.
Main Results:
- BPAF exposure dose-dependently increased serum succinate and hepatic triglyceride (TG) levels.
- Cryo-EM docking revealed BPAF binding to SUCNR1, disrupting its conformation.
- BPAF-exposed macrophages released succinate, which bound to hepatocyte SUCNR1, suppressed Akt phosphorylation, and activated JNK, leading to increased lipid droplets and TG, total cholesterol (TC), and free fatty acids (FFA).
Conclusions:
- The study proposes the first AOP for BPAF-induced hepatic steatosis, involving BPAF-SUCNR1 binding, macrophage succinate release, SUCNR1-mediated signaling disruption, and subsequent lipid accumulation.
- These findings provide critical mechanistic insights into BPAF's role in metabolic disorders.
- The established AOP is valuable for the chemical risk assessment of BPAF and related bisphenols.
