Liver X receptor up-regulates α-tocopherol transfer protein expression and α-tocopherol status

Fat-soluble vitamin E (α-tocopherol) has antioxidant activity. α-Tocopherol transfer protein (α-TTP), a hepatic cytosolic protein, selectively binds α-tocopherol and has an important role regulating circulatory α-tocopherol levels. However, only a few studies have shown the transcriptional regulation of the α-TTP gene. Here, we demonstrate that liver X receptor (LXR) regulates α-TTP expression through direct interaction with the α-TTP gene promoter, and it modulates circulating α-tocopherol levels. LXR belongs to the nuclear receptor superfamily, acts as a ligand-dependent transcription factor for oxysterols and plays an important role in cholesterol metabolism and lipogenesis. We identified an LXR response element (LXRE; DR4, a direct repeat with four-nucleotides spacing) of the human α-TTP gene promoter by using luciferase and electrophoretic mobility shift assays. Mutations in this element abolished activation of this promoter. Moreover, treatment of vitamin E-deficient rats with T0901317, a synthetic LXR ligand, increased α-TTP expression in the liver and cerebrum and increased the plasma α-tocopherol levels. These results indicate that the LXR signaling pathway modulates α-TTP gene expression and plasma α-tocopherol levels. Our observations imply that the LXR signaling pathway might be a useful target for antioxidant properties by controlling the vitamin E status.