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

J Nutr Biochem. 2013 Dec;24(12):2158-67. doi: 10.1016/j.jnutbio.2013.08.008.

Abstract

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.

Keywords: Lipogenesis; Liver X receptor (LXR); α-Tocopherol; α-Tocopherol transfer protein (α-TTP).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Lipogenesis
  • Liver / drug effects
  • Liver / metabolism
  • Liver X Receptors
  • Male
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Promoter Regions, Genetic
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Response Elements / drug effects
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Up-Regulation*
  • Vitamin E Deficiency / drug therapy
  • alpha-Tocopherol / blood*

Substances

  • Carrier Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Sulfonamides
  • T0901317
  • alpha-tocopherol transfer protein
  • alpha-Tocopherol