Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay

The reduction in hepatic abundance of sterol regulatory element binding pro tein-1 (SREBP-1) mRNA and protein associated with the ingestion of polyunsa turated fatty acids (PUFA) appears to be largely responsible for the PUFA-d ependent inhibition of lipogenic gene transcription. Our initial studies in dicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA, Nuclear run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms. In this report we demonstrate that PUF A enhance the decay of both SREBP-1a and -1c, When rat hepatocytes in monol ayer culture were treated with albumin-bound 20:4(n-6) or 20:5(n-3) the hal f-life of total SREBP-1 mRNA was reduced by 50%. Ribonuclease protection as says revealed that the decay of SREBP-1c mRNA was more sensitive to PUFA th an was SREBP-1a, i.e. the half-life of SREBP-1c and -1a was reduced from 10 .0 to 4.6 h and 11.6 to 1.6 h, respectively. Interestingly, treating the he patocytes with the translational inhibitor, cycloheximide, prevented the PU FA-dependent decay of SREBP-1, This suggests that SREBP-1 mRNA may need to undergo translation to enter the decay process, or that the decay process r equires the synthesis of a rapidly turning over protein. Although the mecha nism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined, cloning and sequencing of the 3 ' -untranslated region for the rat SREBP-1 transcript revealed the presence of an A-U-rich region that is characterist ic of a destablizing element.