Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner.

Journal Article (Journal Article)

Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 microg/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), we treated PPARalpha knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPARalpha-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor beta (TRbeta), retinoid X receptor (RXR), and PPARalpha. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.

Full Text

Duke Authors

Cited Authors

  • Adams, AC; Astapova, I; Fisher, FM; Badman, MK; Kurgansky, KE; Flier, JS; Hollenberg, AN; Maratos-Flier, E

Published Date

  • May 7, 2010

Published In

Volume / Issue

  • 285 / 19

Start / End Page

  • 14078 - 14082

PubMed ID

  • 20236931

Pubmed Central ID

  • PMC2863226

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.C110.107375


  • eng

Conference Location

  • United States