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Published on: October 21, 2017
Role of Hepatocyte- and Macrophage-Specific in Hepatotoxicity Induced by Diethylhexyl Phthalate in Mice
Miao Xu1,2, Yongning Li1, Xiaohong Wang1
1National Health Commission (NHC) Key Laboratory of Food Safety Risk Assessment, Chinese Academy of Medical Sciences Research Unit (No. 2019RU014), China National Center for Food Safety Risk Assessment, Beijing, China.
Background:
Phthalates may disturb metabolic homeostasis in the liver by interfering with the peroxisome proliferator-activated receptors (PPARs). However, the role of hepatic macrophages in the lipid metabolic dysregulation induced by diethylhexyl phthalate (DEHP) remains unclear.
Objectives:
We aimed to evaluate the respective role of hepatocyte- and macrophage-specific in the hepatotoxicity induced by DEHP.
Methods:
Wild-type (WT), hepatocyte-specific knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP ( body weight) by daily gavage for 28 d, followed by hepatotoxicity examination and macrophage analysis. RNA sequencing and lipid metabolomic analysis were used to characterize the molecular changes in mouse liver. Mouse bone marrow-derived macrophages (BMDMs) and human monocytic THP-1 cell-derived macrophages were used to investigate the mechanistic regulation of macrophages' polarization by DEHP and mono(2-ethylhexyl) phthalate (MEHP).
Results:
The levels of hepatic steatosis and triglyceride were significantly higher in the mice treated with DEHP compared with the control mice in the WT and Hep-KO model. Lipid accumulation induced by DEHP was notably attenuated in the Mac-KO mice, but M2-polarization of hepatic macrophages in the Mac-KO mice was significantly higher compared with the WT mice under DEHP treatment. The M2-polarization of BMDMs and human macrophages was suppressed by DEHP and MEHP. Transcriptomic and lipidomic data suggested lower levels of lipid biosynthesis, fatty acid oxidation, and oxidative phosphorylation in the Mac-KO mice compared with the WT and Hep-KO mice under DEHP treatment.
Conclusions:
Our data suggested that the orchestrated activation of and by MEHP may reprogram hepatic macrophages' polarization, thereby affecting lipid homeostasis in the mouse liver. Although this conclusion was based on studies conducted in mice and in vitro, these findings may aid in elucidating the health effect of environmental phthalate exposure. https://doi.org/10.1289/EHP9373.
Insights
Diethylhexyl phthalate (DEHP) disrupts liver lipid metabolism. Macrophage-specific PPAR knockout attenuated DEHP-induced lipid accumulation by reprogramming macrophage polarization, suggesting a key role for macrophages in phthalate-induced liver injury.
Area of Science:
- Environmental Health Sciences
- Toxicology
- Metabolic Disease
Background:
- Phthalates, such as diethylhexyl phthalate (DEHP), are environmental contaminants known to disrupt metabolic homeostasis.
- Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid metabolism, and phthalates can interfere with their function.
- The specific role of hepatic macrophages in DEHP-induced lipid metabolic dysregulation remains largely uncharacterized.
Purpose of the Study:
- To investigate the distinct roles of hepatocyte-specific and macrophage-specific PPARs in DEHP-induced hepatotoxicity.
- To elucidate the mechanisms by which DEHP affects lipid metabolism in the liver, with a focus on macrophage involvement.
Main Methods:
- Utilized wild-type (WT), hepatocyte-specific PPAR knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mouse models.
- Administered DEHP via oral gavage for 28 days, followed by hepatotoxicity and macrophage analyses.
- Employed RNA sequencing and lipid metabolomic analysis, alongside in vitro studies using bone marrow-derived macrophages (BMDMs) and THP-1 derived macrophages.
Main Results:
- DEHP treatment significantly increased hepatic steatosis and triglyceride levels in WT and Hep-KO mice.
- Mac-KO mice exhibited attenuated DEHP-induced lipid accumulation and increased M2-polarized hepatic macrophages.
- DEHP and its metabolite MEHP suppressed M2-polarization in both mouse and human macrophages.
- Transcriptomic and lipidomic analyses indicated reduced lipid biosynthesis and fatty acid oxidation in Mac-KO mice.
Conclusions:
- MEHP-mediated activation of PPARs reprograms hepatic macrophage polarization, impacting liver lipid homeostasis.
- Hepatic macrophages play a critical role in mediating DEHP-induced liver lipid dysregulation.
- Findings contribute to understanding the health effects of environmental phthalate exposure.
