Ecnomotopic expression of olfactory receptors is affected by human apolipoproteins A-IMilano and A-II: evidence from liver microarray analyses

Olfactory receptors (ORs) are seven transmembrane domains G protein-coupled receptors (GPCRs) located in the olfactory sensory neurons (OSNs) of the nasal olfactory epithelium. Although OR expression was initially hypothesized to be restricted to the OSNs, an ecnomotopic expression has been identified and associated with the modulation of different physiological functions, such as glucose and lipid metabolism, hypoxia sensing, wound healing and sperm chemiotaxis. However, the role of most ORs in non-olfactory tissues is still a matter of debate, as well as their specific ligands and mechanisms of action. High-density lipoproteins (HDL) are heterogenous, and multifunctional nanoparticles constituted primarily of proteins and lipids. Their main structural protein, namely, apolipoprotein A-I (A-I) has been recognized as the major determinant of the biological activities of HDL. Recently, our group, by using unique mouse models and microarray methodology, has demonstrated that human A-II (hA-II) and A-IMilano (A-IM), a molecular variant of A-I, strongly modulate the hepatic expression of different genes involved in lipid metabolism and immune/inflammatory pathways. Therefore, aiming at investigating the impact of these apolipoproteins on the hepatic expression of mouse ORs (Olfrs), we have performed a new bioinformatic analysis of the differentially expressed genes (DEGs) found in the liver of hA-II/A-I k-in versus hA-II/A-IM k-in; A-IM k-in versus hA-II/A-IM k-in; A-I k-in versus A-IM k-in; A-I k-in versus hA-II/A-I k-in mice. Our results suggest that the presence of A-IM, either alone or in combination with hA-II, is critical for the efficient trafficking and functional expression of Olfrs at the cell surface. Moreover, co-expression of hA-II with A-I resulted in down-regulation of previously uncharacterized Olfrs genes an up-regulation of several known Olfrs, which are likely responsive to short-chain fatty acids and signal through the cAMP/CREB pathway.