Olfactory receptor 10J5 responding to \u03b1-cedrene regulates hepatic steatosis via the cAMP\u2013PKA pathway

Tao Tong,Caroline Bushdid,Claire A De March,Cheil Moon,Jérôme Golebiowski,Yeojin Min,Taesun Park,Sang Eun Ryu

doi:10.1038/s41598-017-10379-x

Abstract

Ectopic expression and functions of odorant receptors (ORs) in the human body have aroused much interest in the past decade. Mouse olfactory receptor 23 (MOR23, olfr16) and its human orthologue, OR10J5, have been found to be functionally expressed in several non-olfactory systems. Here, using MOR23- and OR10J5-expressing Hana3A cells, we identified α-cedrene, a natural compound that protects against hepatic steatosis in mice fed the high-fat diet, as a novel agonist of these receptors. In human hepatocytes, an RNA interference-mediated knockdown of OR10J5 increased intracellular lipid accumulation, along with upregulation of lipogenic genes and downregulation of genes related to fatty acid oxidation. α-Cedrene stimulation resulted in a significant reduction in lipid contents of human hepatocytes and reprogramming of metabolic signatures, which are mediated by OR10J5, as demonstrated by receptor knockdown experiments using RNA interference. Taken together, our findings show a crucial role of OR10J5 in the regulation of lipid accumulation in human hepatocytes.

Highlights

Olfactory receptors (ORs) are seven-transmembrane domain G protein-coupled receptors (GPCRs) that functions as chemosensors within the olfactory epithelium (OE) of the nose, where they detect the small molecules we perceive as odorants[1]
The livers of α-cedrene-fed mice maintained a healthy red color, whereas the livers of high-fat diet (HFD)-fed mice turned whitish (Fig. 1b). In line with these findings, biochemical analysis revealed that the hepatic accumulation of triglyceride, cholesterol, and free fatty acid induced by HFD was significantly decreased by α-cedrene treatment (Fig. 1c)
Olfactory sensory neurons were pretreated with 3-isobutyl-1-methylxanthine (IBMX) for 30 min to inhibit phosphodiesterases, and intracellular cAMP levels were measured after min of odorant mixture (10 μM) or α-cedrene (100 μM) stimulation. (b) Images of Fluo 3-AM fluorescent intensity (488 nm) from olfactory sensory neurons (OSNs) are presented in colors to discriminate increased intracellular calcium levels

Summary

Introduction

Olfactory receptors (ORs) are seven-transmembrane domain G protein-coupled receptors (GPCRs) that functions as chemosensors within the olfactory epithelium (OE) of the nose, where they detect the small molecules we perceive as odorants[1]. The odor information detected by this multiplicity of ORs is processed through a common signaling pathway: when an OR binds to its odorant, it activates a single G protein species, the olfactory trimeric G protein (Golf), which activates the olfactory isoform of adenylate cyclase (Adcy3)[1, 4, 5] These receptors were originally thought to be restricted to the nose[6], it is recognized that ORs are found in a variety of other tissues where they act as sensitive and selective chemoreceptors that influence many physiological processes[2,3,4, 7,8,9,10]. We demonstrate that α-cedrene along with lyral decreases triglyceride accumulation in human hepatocytes through the OR10J5– cAMP–PKA pathway

Methods

Results

Conclusion