Abstract

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 $\text{PPAR}\mathrm{\gamma }$ in the hepatotoxicity induced by DEHP.

Methods:

Wild-type (WT), hepatocyte-specific $\text{PPAR}\mathrm{\gamma }$ knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP ($625\mathrm{mg}/\mathrm{kg}$ 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 $\text{PPAR}\mathrm{\alpha }$ and $\text{PPAR}\mathrm{\gamma }$ 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

中文翻译：

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肝细胞和巨噬细胞特异性 PPARγ 在邻苯二甲酸二乙基己酯诱导小鼠肝毒性中的作用

摘要

背景：

邻苯二甲酸盐可能通过干扰过氧化物酶体增殖物激活受体 (PPAR) 扰乱肝脏中的代谢稳态。然而，肝巨噬细胞在邻苯二甲酸二乙基己酯 (DEHP) 诱导的脂质代谢失调中的作用仍不清楚。

目标：

我们旨在评估肝细胞特异性和巨噬细胞特异性的各自作用 $\text{PPAR}\mathrm{\gamma }$ 在 DEHP 引起的肝毒性中。

方法：

野生型 (WT)，肝细胞特异性 $\text{PPAR}\mathrm{\gamma }$ 敲除 (Hep-KO) 和巨噬细胞特异性 PPAR 敲除 (Mac-KO) 小鼠接受 DEHP ($625\mathrm{毫克}/\mathrm{公斤}$体重）每天灌胃 28 天，随后进行肝毒性检查和巨噬细胞分析。RNA测序和脂质代谢组学分析用于表征小鼠肝脏的分子变化。小鼠骨髓源性巨噬细胞 (BMDMs) 和人单核细胞 THP-1 细胞源性巨噬细胞用于研究 DEHP 和邻苯二甲酸单 (2-乙基己基) 酯 (MEHP) 对巨噬细胞极化的机制调节。

结果：

与 WT 和 Hep-KO 模型中的对照小鼠相比，用 DEHP 治疗的小鼠的肝脂肪变性和甘油三酯水平显着升高。DEHP 诱导的脂质积累在 Mac-KO 小鼠中显着减弱，但与 DEHP 治疗的 WT 小鼠相比，Mac-KO 小鼠中肝巨噬细胞的 M2 极化显着更高。BMDMs 和人类巨噬细胞的 M2 极化被 DEHP 和 MEHP 抑制。转录组学和脂质组学数据表明，与 DEHP 处理的 WT 和 Hep-KO 小鼠相比，Mac-KO 小鼠的脂质生物合成、脂肪酸氧化和氧化磷酸化水平较低。

结论：

我们的数据表明，协调的激活 $\text{PPAR}\mathrm{\alpha }$ 和 $\text{PPAR}\mathrm{\gamma }$MEHP 可能会重新编程肝巨噬细胞的极化，从而影响小鼠肝脏中的脂质稳态。尽管这一结论是基于在小鼠和体外进行的研究，但这些发现可能有助于阐明环境中邻苯二甲酸盐暴露对健康的影响。https://doi.org/10.1289/EHP9373