气候变化领域集成服务门户(CCPortal): Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease

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DOI	10.1073/pnas.2017129117
	Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease
	Yueh M.-F.; He F.; Chen C.; Vu C.; Tripathi A.; Knight R.; Karin M.; Chen S.; Tukey R.H.
发表日期	2020
ISSN	0027-8424
起始页码	31259
结束页码	31266
卷号	117 期号:49
英文摘要	Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFDinduced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-altered Fgf21 expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of the Fgf21 gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Diabetes; High-fat diet; Nonalcoholic steatohepatitis; Toxicant-associated steatohepatitis
语种	英语
scopus关键词	activating transcription factor 4; fibroblast growth factor 21; lipid; peroxisome proliferator activated receptor alpha; triclosan; animal cell; animal experiment; animal model; animal tissue; Article; Bacteroidetes; controlled study; disease course; experimental liver fibrosis; experimental steatohepatitis; feces analysis; Fgf21 gene; Firmicutes; lipid diet; lipid liver level; male; microbial community; microbial diversity; mouse; newborn; nonalcoholic fatty liver; nonhuman; nutritional disorder; oxidative stress; pathogenesis; priority journal; species richness; transcription regulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160193
作者单位	Yueh, M.-F., Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, CA 92093, United States; He, F., Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, CA 92093, United States; Chen, C., Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, CA 92093, United States; Vu, C., Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, CA 92093, United States; Tripathi, A., Department of Pediatrics, University of California, San Diego, CA 92093, United States; Knight, R., Department of Pediatrics, University of California, San Diego, CA 92093, United States; Karin, M., Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, CA 92093, United States; Chen, S., Laboratory of Environmental Toxicology, Department of Pharmacology, Uni...
推荐引用方式 GB/T 7714	Yueh M.-F.,He F.,Chen C.,et al. Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease[J],2020,117(49).
APA	Yueh M.-F..,He F..,Chen C..,Vu C..,Tripathi A..,...&Tukey R.H..(2020).Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease.Proceedings of the National Academy of Sciences of the United States of America,117(49).
MLA	Yueh M.-F.,et al."Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease".Proceedings of the National Academy of Sciences of the United States of America 117.49(2020).