Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 49, Pages 31259-31266Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2017129117
Keywords
toxicant-associated steatohepatitis; nonalcoholic steatohepatitis; high-fat diet; diabetes
Categories
Funding
- National Institute of Environmental Health Sciences [ES010337]
- NIH [R21-ES023906, R21-AI135677, GM126074, CA211794, CA198103, DK120714]
- Eli Lilly
- Center for Microbiome Innovation
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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 PPAR alpha, 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.
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