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

作者：Wu Chunyan; Jia Yaoyao; Lee Ji Hae; Kim Yeonji; Sekharan Sivakumar; Batista Victor S; Lee Sung Joon^*

来源：International Journal of Biochemistry & Cell Biology, 2015, 64: 75-80.

DOI：10.1016/j.biocel.2015.03.008

• Olfactory receptor
• OR1A1
• PKA
• CREB
• Lipid metabolism

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-gamma (PPAR-gamma) in hepatocytes. In (-)-carvone-stimulated cells, the repression of PPAR-gamma 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.

• 出版日期2015-7