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. 2020 Dec 8;117(49):31259-31266.
doi: 10.1073/pnas.2017129117. Epub 2020 Nov 23.

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease

Mei-Fei Yueh  1 , Feng He  2 , Chen Chen  1 , Catherine Vu  1 , Anupriya Tripathi  3 , Rob Knight  3 , Michael Karin  4 , Shujuan Chen  1 , Robert H Tukey  5
Affiliations

Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease

Mei-Fei Yueh et al. Proc Natl Acad Sci U S A. .

Abstract

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.

Keywords: diabetes; high-fat diet; nonalcoholic steatohepatitis; toxicant-associated steatohepatitis.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
TCS in combination with the high-fat diet (HFD) significantly blunted HFD-induced Fgf21, activated hepatic amino acid response (AAR), caused dyslipidemia, and altered triglycerides biosynthesis. Mice were fed with a chow diet, a chow diet containing TCS, an HFD, or an HFD containing TCS for 4 to 4.5 mo. (A and B) Hepatic FGF21 mRNA levels were measured by real-time PCR, and serum FGF21 levels were evaluated by the ELISA. (C) Mice were fed with an HFD containing either vehicle (DMSO) or TCS. Expression of hepatic genes involved in the AAR (Trib3, Asns) and genes associated with amino acid metabolism (Bckdk, Hpd) were evaluated by real-time PCR. (D) TCS increased lipid droplet accumulation in both a chow diet and HFD. (E) Under an HFD, TCS altered expression of genes associated with fatty acid uptake and lipogenesis. (F) TCS elevated serum triglyceride levels. (G) Under an HFD, TCS-treated mice had higher amounts of abdominal white adipose tissue.
Fig. 2.
Fig. 2.
TCS impaired liver function, exasperated steatohepatitis, and impacted microbiota composition in the study using the type I diabetic animal model. Male neonatal mice were administered with streptozotocin (STZ) followed by high-fat diet (HFD) feeding, containing either vehicle (ctrl) or TCS, for ∼10 wk after they were weaned. (A) Serum ALT levels. (B) Hepatic lipid droplets detected by Oil Red O staining. (C) Histological analysis with H&E staining. (D) Expression of genes, including (i) Ho-1, Gsta1, Gsta2, (ii) Tnfα, Il-8, and (iii) Collagen 1a1, Timp1, was quantitated using real-time PCR. (E) Representative Sirius red staining of liver sections shows collagen deposition, indicating fibrosis progression in the TCS-treated mice compared with control mice. (F and G) STZ-injected male mice (14 wk old) were subjected to a chow diet containing vehicle (Ctrl) or TCS, or a high-fat diet containing vehicle (HFD) or TCS (HFD + TCS). (F) Microbial diversity analysis revealed that an HFD led to decreases in bacterial diversity, and TCS further significantly reduced the species diversity in the gut microbial community. (G) The HFD group had decreased fecal Bacteroidetes and increased Firmicutes, and the changes were synergistically enlarged when mice were fed an HFD containing TCS.
Fig. 3.
Fig. 3.
ATF4 is highly induced in TCS-treated mice and is required for TCS-induced dyslipidemia. (A). Mice (n = 4) were subjected to a high-fat diet (HFD) containing either vehicle (Ctrl) or TCS. Hyperactivation of ATF4 at the protein level (Left) and phosphorylation of eukaryotic translation initiation factor 2A (eIF2A) (Right) by TCS detected by Western blotting. (B–E) Atf4F/Fand Atf4ΔHep mice were fed an HFD containing either vehicle or TCS. (B) Oil Red O staining shows that lipid droplets were significantly reduced in the liver slide obtained from Atf4ΔHep mice. (C) The abdominal fat content in the control Atf4F/F or Atf4ΔHep mice, with two representatives of each group shown in the pictures. (D) Fgf21 gene expression was determined by real-time PCR. (E and F) Real-time PCR analysis of genes impacted by TCS.
Fig. 4.
Fig. 4.
Induction of Cyp4a14 by TCS is PPARα dependent. (A) Mice (Pparαwt or Pparα−/−) were subjected to a chow diet containing vehicle (Ctrl) or TCS, or a high-fat diet (HFD) containing vehicle (Ctrl) or TCS. TCS-induced Cyp4a14 expression was diminished in Ppaα knockout mice (Left). Ffg21 expression regulated by an HFD and HFD/TCS is PPARα dependent (Right). (B) Mice (Pparαwt or Pparα−/−) were subjected to a HFD-containing vehicle (Ctrl) or TCS. PPARα-dependent gene regulation was detected by real-time PCR.
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