Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes

Int J Biochem Cell Biol. 2015 Jul:64:75-80. doi: 10.1016/j.biocel.2015.03.008. Epub 2015 Mar 25.

Abstract

Olfactory receptors (ORs) comprise the largest G protein-coupled receptor gene superfamily. Recent studies indicate that ORs are also expressed in non-olfactory organs, including metabolically active tissues, although their biological functions in these tissues are largely unknown. In this study, OR1A1 expression was detected in HepG2 liver cells. OR1A1 activation by (-)-carvone, a known OR1A1 ligand, increased the cyclic adenosine monophosphate (cAMP), but not intracellular Ca(2+) concentration, thereby inducing protein kinase A (PKA) activity with subsequent phosphorylation of cAMP response element-binding protein (CREB) and upregulation of the CREB-responsive gene hairy and enhancer of split (HES)-1, a corepressor of peroxisome proliferator-activated receptor-γ (PPAR-γ) in hepatocytes. In (-)-carvone-stimulated cells, the repression of PPAR-γ reduced the expression of the target gene, mitochondrial glycerol-3-phosphate acyltransferase, which encodes a key enzyme involved in triglyceride synthesis. Intracellular triglyceride level and lipid accumulation were reduced in cells stimulated with (-)-carvone, effects that were diminished following the loss of OR1A1 function. These results indicate that OR1A1 may function as a non-redundant receptor in hepatocytes that regulates the PKA-CREB-HES-1 signaling axis and thereby modulates hepatic triglyceride metabolism.

Keywords: CREB; Lipid metabolism; OR1A1; Olfactory receptor; PKA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Membrane / metabolism
  • Cyclic AMP / metabolism
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Odorant / metabolism*
  • Signal Transduction
  • Transcription Factor HES-1
  • Triglycerides / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • OR1A1 protein, human
  • PPAR gamma
  • Receptors, Odorant
  • Transcription Factor HES-1
  • Triglycerides
  • HES1 protein, human
  • Cyclic AMP
  • Proto-Oncogene Proteins c-akt