Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease
| Autor: | Chen Chen, Feng He, Mei-Fei Yueh, Anupriya Tripathi, Catherine Vu, Shujuan Chen, Michael Karin, Robert H. Tukey, Rob Knight |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Liver Cirrhosis
FGF21 medicine.disease_cause Oral and gastrointestinal Hepatitis Mice Liver disease Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease 2.1 Biological and endogenous factors nonalcoholic steatohepatitis Aetiology Multidisciplinary diabetes Liver Disease Fatty Acids Fatty liver Biological Sciences high-fat diet Liver medicine.medical_specialty toxicant-associated steatohepatitis Chronic Liver Disease and Cirrhosis Biology Diet High-Fat Internal medicine Genetics medicine Animals Humans PPAR alpha Obesity Life Below Water Metabolic and endocrine Nutrition Animal fungi medicine.disease Triclosan Diet Fibroblast Growth Factors High-Fat Disease Models Animal Endocrinology Gene Expression Regulation Disease Models Steatosis Steatohepatitis Digestive Diseases Oxidative stress Homeostasis |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 49 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 HFD-induced 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. |
| Databáze: | OpenAIRE |
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