Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes |
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Institution: | 1. Department of Biochemistry and Functional Proteomics, Faculty of Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany;2. Department of Cell Physiology, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany;3. Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Otto-Hahn-Str. 6b, 44227 Dortmund, Germany;4. Department of Pharmacology and Toxicology, University of Jena, Drackendorfer Str. 1, 07747 Jena, Germany |
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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 Ca2+ 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. |
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Keywords: | Olfactory receptor OR1A1 PKA CREB Lipid metabolism |
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