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

Wu, Chunyan, Jia, Yaoyao, Lee, Ji Hae, Kim, Yeonji, Sekharan, Sivakumar, Batista, Victor S., Lee, Sung-Joon
The international journal of biochemistry & cell biology 2015 v.64 pp. 75-80
G-protein coupled receptors, cAMP-dependent protein kinase, calcium, cyclic AMP, genes, glycerol-3-phosphate acyltransferase, hepatocytes, ligands, metabolism, mitochondria, olfactory receptors, phosphorylation, tissues, triacylglycerols
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.