Propiconazole is a triazole fungicide previously shown to induce triglyceride accumulation in human liver HepaRG cells, potentially via activation of the Pregnane X Receptor (PXR). However, whether propiconazole can disrupt hepatic and whole-body metabolism in vivo is currently unknown. Therefore, we aimed to examine the metabolic effects of propiconazole in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. To this end, male C57BL/6J mice were fed a high-fat diet for 20 weeks. During the last 10 weeks, mice additionally received vehicle, 0.04, 30, or 100 mg/kg body weight (bw)/day propiconazole via oral gavage. High-dose propiconazole, but not low or intermediate dose, reduced body weight gain and adipose tissue weight in obese mice. Mice receiving high-dose propiconazole displayed improved glucose tolerance and reduced levels of plasma triglycerides and cholesterol. Propiconazole dose-dependently increased liver weight and triglyceride levels and at high dose caused signs of hepatic inflammation. RNA sequencing on the liver revealed that propiconazole mainly induced PXR target genes. At intermediate and high dose, propiconazole induced pathways related to cell-cell interactions and inflammation, while oxidative phosphorylation was repressed by propiconazole. Comparison of gene regulation in wildtype and PXR knockout primary hepatocytes as well as gene reporter assays confirmed the activation of PXR by propiconazole. All in all, our data underscore the capacity of propiconazole to activate PXR in the liver and thereby promote the development of hepatic steatosis in vivo.

• Keywords
• Lipid metabolism, Liver, MASLD, Metabolism disrupting chemicals (MDCs), Nuclear receptors/PXR, Propiconazole,
• MeSH
• Diet, High-Fat adverse effects   MeSH
• Insulin Resistance MeSH
• Liver drug effects   metabolism   pathology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity * chemically induced   metabolism   etiology   MeSH
• Pregnane X Receptor * metabolism   genetics   MeSH
• Fungicides, Industrial * toxicity   administration & dosage   MeSH
• Triazoles * toxicity   administration & dosage   MeSH
• Triglycerides blood   MeSH
• Dose-Response Relationship, Drug MeSH
• Fatty Liver * chemically induced   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Pregnane X Receptor * MeSH
• propiconazole MeSH Browser
• Fungicides, Industrial * MeSH
• Triazoles * MeSH
• Triglycerides MeSH