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.
Department of Pediatrics, Osaka Medical College, Osaka 569-8686, Japan.
Maki
M
Koh
Kimitaka
K
Takitani
Hiroshi
H
Miyazaki
Shigeo
S
Yamaoka
Hiroshi
H
Tamai
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D014811:Vitamin E Deficiency / Q000188:drug therapy; D024502:alpha-Tocopherol / Q000097:blood*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D002352:Carrier Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D024502:alpha-Tocopherol; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C017763:alpha-tocopherol transfer protein
Lipogenesis; Liver X receptor (LXR); α-Tocopherol; α-Tocopherol transfer protein (α-TTP)