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标题：Role of Hepatocyte- and Macrophage-Specific P P A R γ in Hepatotoxicity Induced by Diethylhexyl Phthalate in Mice
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作者：Miao Xu ; Yongning Li ; Xiaohong Wang 等
期刊名称：Environmental Health Perspectives
印刷版ISSN：0091-6765
电子版ISSN：1552-9924
出版年度：2022
卷号：130
期号：1
DOI：10.1289/EHP9373
语种：English
出版社：OCR Subscription Services Inc
摘要：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 PPAR γ in the hepatotoxicity induced by DEHP. Methods: Wild-type (WT), hepatocyte-specific PPAR γ knockout (Hep-KO), and macrophage-specific PPAR knockout (Mac-KO) mice were administered DEHP ( 625 mg / 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 PPAR α and PPAR γ 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