Activation of epithelial growth factor receptor pathway by unsaturated fatty acids

Nonesterified fatty acids (NEFAs) are acutely liberated during lipolysis an d are chronically elevated in pathological conditions, such as insulin resi stance, hypertension, and obesity, which are known risk factors for atheros clerosis. The purpose of this study was to investigate the effect and mecha nism of action of NEFAs on the epithelial growth factor (EGF) receptor (EGF R). In the ECV-304 endothelial cell line, unsaturated fatty acids triggered a time- and dose-dependent tyrosine phosphorylation of EGFR (polyunsaturat ed fatty acids [PUFAs] were the most active), whereas saturated FAs were in active. Although less potent than PUFAs, oleic acid (OA) was used because i t is prominent in the South European diet and is only slightly oxidizable ( thus excluding oxidation derivatives). EGFR is activated by OA independent of any autocrine secretion of EGF or other related mediators. OA-induced EG FR autophosphorylation triggered EGFR signaling pathway activation (as asse ssed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and S HP-2) and subsequent p42/p44 mitogen-activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK(+) cell lines). OA induced in vitro both autophosphorylation and activation of intrinsic ty rosine kinase of immunopurified EGFR, thus suggesting that EGFR is a primar y target of OA. EGFR was also activated by mild surfactants, Tween-20 and T riton X-100, both in vitro (on immunopurified EGFR) and in intact living ce lls, thus indicating that EGFR is sensitive to amphiphilic molecules. These data suggest that EGFR is activated by OA and PUFAs, acts as a sensor for unsaturated fatty acids (and amphiphilic molecules), and is a potential tra nsducer by which diet composition may influence vascular wall biology.