title: Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes.
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.
authors: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, BK21-PLUS, Korea University, Seoul 136-713, Republic of Korea.
authors: Chunyan
authors: C
authors: Wu
authors: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, BK21-PLUS, Korea University, Seoul 136-713, Republic of Korea.
authors: Yaoyao
authors: Y
authors: Jia
authors: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, BK21-PLUS, Korea University, Seoul 136-713, Republic of Korea.
authors: Ji Hae
authors: JH
authors: Lee
authors: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, BK21-PLUS, Korea University, Seoul 136-713, Republic of Korea.
authors: Yeonji
authors: Y
authors: Kim
authors: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors: Sivakumar
authors: S
authors: Sekharan
authors: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors: Victor S
authors: VS
authors: Batista
authors: Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, BK21-PLUS, Korea University, Seoul 136-713, Republic of Korea. Electronic address: junelee@korea.ac.kr.
authors: Sung-Joon
authors: SJ
authors: Lee
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018035:Receptors, Odorant / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000242:Cyclic AMP; D018398:Homeodomain Proteins; D047495:PPAR gamma; D051057:Proto-Oncogene Proteins c-akt; D018035:Receptors, Odorant; D000072056:Transcription Factor HES-1; D014280:Triglycerides; C525018:OR1A1 protein, human; C078493:HES1 protein, human
keywords: CREB; Lipid metabolism; OR1A1; Olfactory receptor; PKA