Reduced active sterol regulatory element binding protein‐1 (SREBP‐1) and delta‐6 desaturase transcription are accompanied by increased membrane phosphatidyl‐ethanolamine (PE) / phosphatidyl‐choline (PC) ratio

Abstract

SREBP‐1 regulates delta‐6 desaturase (D6D), the key enzyme of highly unsaturated fatty acid synthesis. While PE suppresses proteolytic activation of SREBP in Drosophila, an activation mechanism of SREBP‐1 is unknown in mammals. Dietary ethanolamine (EA) and eritadenine (ER), which increase membrane PE/PC ratio, suppress D6D activity and mRNA in rat liver. We tested the hypothesis that both EA and ER suppress D6D gene transcription by reducing active form of SREBP‐1 (nSREBP‐1). First, rats (n=6) were fed a control diet or a diet supplemented with either EA (8g/kg) or ER (50 mg/kg) for 14 days. Both EA and ER supplementation decreased D6D mRNA and nSREBP‐1 in livers (p<0.05). Second, HepG2 cells treated with EA (30μM) and ER (1mM) significantly reduced D6D mRNA and nSREBP‐1 with concomitant increase in the PE/PC ratio. Next, D6D promoter‐luciferase reporter constructs were transfected into HepG2 cells, and then treated with EA and ER. Promoter activity was suppressed in constructs with wild‐type D6D promoters by EA and ER treatments, whereas mutation of sterol regulatory element abolished or reduced the suppression by EA or ER, respectively. In conclusion, SREBP‐1 in part mediates suppression of D6D gene transcription by EA and ER with an accompanying increase in the PE/PC ratio, suggesting that like in Drosophila, SREBP‐1 activation in mammals may also be regulated by the membrane PE/PC ratio.