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标题：Association between Arsenic Suppression of Adipogenesis and Induction of CHOP10 via the Endoplasmic Reticulum Stress Response
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作者：Yongyong Hou ; Peng Xue ; Courtney G. Woods 等
期刊名称：Environmental Health Perspectives
印刷版ISSN：0091-6765
电子版ISSN：1552-9924
出版年度：2013
卷号：121
期号：2
页码：237-243
DOI：10.1289/ehp.1205731
出版社：OCR Subscription Services Inc
摘要：Ba c k g r o u n d: There is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis.oB j e c t i v e: We sought to determine the mechanisms of arsenic suppression of adipogenesis.Me t h o d s: The effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue–derived stem cells (ADSCs).re s u l t s: Exposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ≤ 5 μM), inorganic arsenate (≤ 20 μM), trivalent monomethylated arsenic (MMA3+, ≤ 1 μM), and trivalent dimethylated arsenic (DMA3+, ≤ 2 μM) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein β(C/EBPβ), which regulates the transcription of peroxi some proliferator-activated receptor γand C/EBPα.co n c l u s i o n s: Low-level iAs and MMA3+trigger the ER stress response and up-reg ulate CHOP10, which inhibits C/EBPβtranscriptional activity, thus suppressing adipogenesis. Arsenic-induced dys-functional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.
关键词：adipogenesis; arsenic; C/EBP; CHOP10; preadipocytes; type 2 diabetes.