Vitamin D inhibits tamoxifen-induced non-alcoholic fatty liver disease through a nonclassical estrogen receptor/liver X receptor pathway

Non-alcoholic Fatty Liver Disease (NAFLD) is one of the common side effects of tamoxifen treatment for estrogen receptor-positive breast cancer, and is representative of disorders of energy metabolism. Fatty liver is induced after tamoxifen (TAM) inhibition of estrogen receptor activity, but the exact mechanism is not clear. This study investigated the effects and mechanisms of TAM-induced steatosis in the liver. The effects and mechanisms of TAM on hepatocyte lipid metabolism were assessed using C57BL/6 female mice and human hepatoma cells. TAM promoted fat accumulation in the liver by upregulation of Srebp-1c expression. Regarding the molecular mechanism, TAM promoted the recruitment of the auxiliary transcriptional activator, p300, and dissociated the auxiliary transcriptional repressor, nuclear receptor corepressor (NCOR), of the complexes, which led to enhancement of Srebp-1c transcription and an increase of triglyceride (TG) synthesis. Vitamin D (VD), a common fat-soluble vitamin, can decrease TAM-induced NAFLD by promoting p300 dissociation and NCOR recruitment. Tamoxifen promoted the recruitment and dissociation of co-transcription factors on the LXR/ER/RXR receptor complex, leading to a disorder of liver lipid metabolism. VD interfered with TAM-induced liver lipid metabolism disorders by reversing this process.