Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound tran scription factors that increase the synthesis of fatty acids as well as cho lesterol in animal cells. All three SREBP isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their prote olytic release from membranes. Previous data indicate that the SREBPs are a lso negatively regulated by unsaturated fatty acids, but the mechanism is u ncertain. In the current experiments, unsaturated fatty acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic k idney (HEK)-293 cells. The potency of unsaturated fatty acids increased wit h increasing chain length and degree of unsaturation, Oleate, linoleate, an d arachidonate were all effective, but the saturated fatty acids palmitate and stearate were not effective, Downregulation occurred at two levels, The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteo lytic processing of these SREBPs was inhibited, When SREBP-1a was produced by a cDNA expressed from an independent promoter, unsaturated fatty acids r educed nuclear SREBP-1a without affecting the mRNA level. There was no effe ct when the cDNA encoded a truncated version that was not membrane-bound, W hen administered together, sterols and unsaturated fatty acids potentiated each other in reducing nuclear SREBP-1, In the absence of fatty acids, ster ols did not cause a sustained reduction of nuclear SREBP-1, but they did re duce nuclear SREBP-2, We conclude that unsaturated fatty acids, as well as sterols, can downregulate nuclear SREBPs and that unsaturated fatty acids h ave their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas ste rols have their greatest inhibitory effects on SREBP-2.