A novel pathway to enhance adipocyte differentiation of 3T3-L1 cells by up-regulation of lipocalin-type prostaglandin D synthase mediated by liver X receptor-activated sterol regulatory element-binding protein-1c

J Biol Chem. 2007 Jun 22;282(25):18458-18466. doi: 10.1074/jbc.M701141200. Epub 2007 Apr 17.

Abstract

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is expressed in adipocytes and is proposed to be involved in the regulation of glucose tolerance and atherosclerosis in type 2 diabetes, because L-PGDS gene knock-out mice show abnormalities in these functions. However, the role of L-PGDS and the regulation mechanism governing its gene expression in adipocytes remain unclear. Here, we applied small interference RNA of L-PGDS to mouse 3T3-L1 cells and found that it suppressed differentiation of these cells into adipocytes. Reporter analysis of the mouse L-PGDS promoter demonstrated that a responsive element for liver receptor homolog-1 (LRH-1) at -233 plays a critical role in preadipocytic 3T3-L1 cells. Moreover, we identified two sterol regulatory elements (SREs) at -194 to be cis-elements for activation of L-PGDS gene expression in adipocytic 3T3-L1 cells. L-PGDS mRNA was induced in response to synthetic liver X receptor agonist, T0901317, through activation of the expression of SRE-binding protein-1c (SREBP-1c) in the adipocytic 3T3-L1 cells. The results of electrophoretic mobility shift assay and chromatin immunoprecipitation assay revealed that LRH-1 and SREBP-1c bound to their respective binding elements in the promoter of L-PGDS gene. Small interference RNA-mediated suppression of LRH-1 or SREBP-1c decreased L-PGDS gene expression in preadipocytic or adipocytic 3T3-L1 cells, respectively. These results indicate that L-PGDS gene expression is activated by LRH-1 in preadipocytes and by SREBP-1c in adipocytes. Liver X receptor-mediated up-regulation of L-PGDS through activation of SREBP-1c is a novel path-way to enhance adipocyte differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Animals
  • Base Sequence
  • Cell Differentiation
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation*
  • Hydrocarbons, Fluorinated
  • Intramolecular Oxidoreductases / chemistry
  • Intramolecular Oxidoreductases / metabolism*
  • Lipocalins
  • Liver X Receptors
  • Mice
  • Molecular Sequence Data
  • Orphan Nuclear Receptors
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sulfonamides / pharmacology
  • Up-Regulation*

Substances

  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Lipocalins
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • TO-901317
  • Intramolecular Oxidoreductases
  • prostaglandin R2 D-isomerase