Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet

J Nutr Biochem. 2012 Jul;23(7):785-90. doi: 10.1016/j.jnutbio.2011.03.023. Epub 2011 Sep 1.


Cholesterol homeostasis is regulated by the liver X receptor (LXR) at the transcriptional level, but it remains unknown whether LXR can affect expression levels of intrahepatic lipolysis related gene. Recent evidence has demonstrated that fibroblast growth factor 21 (FGF21) regulates hepatic lipolysis and fatty acid utilization. In the present study, we examined the role of LXR in FGF21 gene expression associated with regulation of cross-talk signals between cholesterol and triglyceride metabolism in the liver. An in vivo cholesterol feeding test revealed that intake of excess cholesterol increased cholesterol catabolism related gene expression as well as fatty-acid biosynthesis related gene expression. Moreover, the accumulated cholesterol suppressed FGF21 and hormone-sensitive lipase (HSL) gene expression. After 15-day cholesterol feeding, hepatic triglyceride concentrations were negatively correlated with expression levels of the FGF21 and HSL genes in the liver. An LXR agonist (TO-901317) repressed the FGF21 gene expression in mouse primary hepatocytes and HepG2 cells. A promoter deletion study and electrophoretic mobility shift assay revealed that the human FGF21 promoter has at least one LXR response element located from -37 to -22 bp. In summary, LXR represses FGF21 gene expression at the transcription level and might suppress lipolysis and lipid utilization to protect the liver from excess accumulation of toxic cholesterol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Cholesterol, Dietary / adverse effects*
  • Fatty Liver / chemically induced
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology*
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Lipolysis
  • Liver / metabolism
  • Liver X Receptors
  • Male
  • Mice
  • Orphan Nuclear Receptors / metabolism*
  • Promoter Regions, Genetic
  • Response Elements
  • Signal Transduction
  • Sterol Esterase / genetics
  • Sterol Esterase / metabolism
  • Triglycerides / blood


  • Blood Glucose
  • Cholesterol, Dietary
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Triglycerides
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Sterol Esterase