Myclobutanil-mediated alteration of liver-gut FXR signaling in mice

Abstract

The effects of exposure to Myclobutanil, a tri-azole fungicide, on the development and progression of non-alcoholic fatty liver disease (NAFLD) are unclear, but activation of nuclear receptors (NRs) are a known mechanism of azole-induced liver toxicity. Farnesoid x receptor (FXR) is a NR and is highly expressed in the liver and intestine. Activation of FXR tightly regulates bile acid (BA), lipid and glucose homeostasis, and inflammation partly through the induction of fibroblast growth factor 15 (FGF15; human ortholog FGF19). FXR activation is downregulated during NAFLD and agonists are currently being explored as potential therapeutic strategy. In this study, we aimed to clarify the effects of Myclobutanil exposure on FXR activation and NAFLD development. Reporter assay showed Myclobutanil treatment, following FXR activation with potent FXR agonist (GW4064), resulted in a dose-dependent decrease of FXR activity. Furthermore, a 10-day study in male mice demonstrated that co-treatment with Myclobutanil led to an 80% reduction of GW4064-induced ileal expression of Fgf15. In a diet induced NAFLD study, low-fat diet fed mice administered myclobutanil displayed decreased FXR activity in liver and ileum, while high-fat-high-sugar-diet fed mice showed an increase in hepatic FXR activity and an induction of target genes regulated by constitutive androstane receptor and/or pregnane X receptor. Our work demonstrates Myclobutanil inhibits FXR activity and modulates FXR activity differentially in mice fed low-fat diet or high-fat high-sugar diet. Our studies suggest an importance of understanding how Myclobutanil could contribute to BA dysregulation in disease states such as NAFLD.

Sex, Nutrition, and NAFLD: Relevance of Environmental Pollution

“…In treated mice, insecticides such as fipronil (a phenylpyrazole commonly used in agricultural and veterinary fields) and thiamethoxam (a major compound of neonicotinoids) alter lipid metabolism by increasing Pparγ and Fasn expression and promote the generation of oxidative stress and inflammation by decreasing Pparα and Gnmt (glycine n-methyltransferase), ultimately contributing to NAFLD and liver injury [ 93 , 94 ]. Fungicides such as myclobutanil and mancozeb contribute to hepatic lipid deposition, cellular damage, and NAFLD development and progression [ 95 , 96 , 97 ]. In mouse liver, the effects of Myclobutanil can be differently mediated by the signaling of FXR depending on nutritional conditions [ 95 ].…”

“…Fungicides such as myclobutanil and mancozeb contribute to hepatic lipid deposition, cellular damage, and NAFLD development and progression [ 95 , 96 , 97 ]. In mouse liver, the effects of Myclobutanil can be differently mediated by the signaling of FXR depending on nutritional conditions [ 95 ]. In HepG2 cells, myclobutanil, mancozeb, and other fungicides such as tributyltin (TBT) induce steatosis also via retinoid X receptor alpha (RXRα), and hepatotoxicity by decreasing the expression of anti-apoptotic markers [ 96 , 97 , 98 ].…”

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

“…However, currently, there are no specific drugs available for the treatment of NAFLD [ 1 , 2 ]. The farnesoid X receptor (FXR) is a ligand-activated transcription factor, highly expressed in the liver and intestine, which has shown promising clinical results in the treatment of non-alcoholic steatohepatitis (NASH) [ 3 , 4 , 5 ]. Numerous FXR agonists that have been developed for the treatment of NAFLD are in preclinical and clinical trials at present.…”