Di‐(2‐ethylhexyl) phthalate (DEHP) promoted hepatic lipid accumulation by activating Notch signaling pathway

Abstract Di‐(2‐ethylhexyl) phthalate (DEHP) and mono‐2‐ethylhexyl phthalate (MEHP) can induce hepatic lipid metabolism disorders, while the molecular mechanism still remain unknown. We aim to explore the underlying mechanism of Notch signaling pathway on hepatic lipid accumulation induced by DEHP/MEHP. A total of 40 male wistar rats were exposed to DEHP (0, 5, 50, and 500 mg/kg/d) for 8 weeks, BRL‐3A hepatocytes were exposed to MEHP (0, 10, 50, 100, and 200 μM) for 24 h. About 50 μM DAPT and 100 μg/mL Aspirin were used to inhibit Notch pathway and prevent inflammation, respectively. Real‐Time PCR was performed to detect the mRNA expression, western blot and immunofluorescence were used to detect the protein expression. Lipids and inflammatory factors levels were determined by commercial kits. The results showed that DEHP/MEHP promoted the expression of Notch pathway molecules and lipids accumulation in rat livers/BRL‐3A cells. The up‐regulated Notch receptors were correlated with the TG levels in the rat liver. MEHP increased the levels of IL‐8 and IL‐1β. The lipids levels were reduced after anti‐inflammation. The inhibition of Notch pathway reversed the elevation of inflammation and lipid accumulation caused by MEHP. In conclusion, this study demonstrated that DEHP/MEHP led to lipid accumulation in hepatocytes by up‐regulating Notch pathway and the inflammation might play a key role in the process.