Effect of the TYK-2/STAT-3 pathway on lipid accumulation induced by mono-2-ethylhexyl phthalate

Mol Cell Endocrinol. 2019 Mar 15;484:52-58. doi: 10.1016/j.mce.2019.01.012. Epub 2019 Jan 17.


Background: Mono-2-ethylhexyl phthalate (MEHP), an important metabolite of di (2-ethylhexyl) phthalate (DEHP), can induce lipid metabolic disorder. Previous studies have shown that MEHP promotes 3T3-L1 cell differentiation; however, the underlying mechanism is unclear. The present study was performed to investigate the effect of the TYK-2/STAT-3 pathway on lipid accumulation induced by MEHP.

Methods: A 3T3-L1 precursor adipocyte differentiation model was exposed to MEHP. 3-Isobutyl-1-methylxanthine (IBMX), dexamethasone (DEX), and insulin were used to establish the 3T3-L1 precursor adipocyte differentiation model. Then the model cells were exposed to MEHP for 8 d. The lipid droplet formation in 3T3-L1 cells was determined with Oil-Red-O staining, and isopropyl alcohol was used to extract the lipid droplets for quantification. Flow cytometry was used to detect the intracellular reactive oxygen species (ROS) and mitochondrial membrane potential. Quantitative real-time polymerase chain reaction (qPCR) was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by TYK-2/STAT-3 pathway genes and adipogenesis-related genes.

Results: MEHP treatment, compared with the control treatment, significantly promoted the differentiation of 3T3-L1 cells and increased the expression of STAT-3 mRNA and protein and P-STAT3 protein in the cells. In addition, MEHP down-regulated the phosphorylation of STAT-3 in mitochondria. MEHP was found to influence the mitochondrial membrane potential and intracellular ROS levels.

Conclusion: MEHP may affect adipocyte differentiation and lead to lipid accumulation through the TYK-2/STAT-3 pathway.

Keywords: 3T3-L1 adipocytes; Lipid metabolism; MEHP; Mitochondrial STAT-3; ROS; TYK-2/STAT-3 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Cell Differentiation
  • Cell Survival
  • Dexamethasone / pharmacology
  • Diethylhexyl Phthalate / analogs & derivatives*
  • Diethylhexyl Phthalate / pharmacology
  • Insulin / pharmacology
  • Lipid Droplets / metabolism
  • Lipid Metabolism / drug effects*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Reactive Oxygen Species / metabolism
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • TYK2 Kinase / metabolism


  • Insulin
  • Reactive Oxygen Species
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Dexamethasone
  • Diethylhexyl Phthalate
  • TYK2 Kinase
  • Tyk2 protein, mouse
  • mono-(2-ethylhexyl)phthalate
  • 1-Methyl-3-isobutylxanthine