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

Dietary polyunsaturated fatty acids (PUFA), particularly the n-3 PUFA family, protect against the development of insulin resistance by lowering tissue and circulating triglyceride levels. PUFA modulate lipid metabolism by regulating expression of the genes involved in lipid synthesis and oxidation. PUFA suppress the expression of the genes responsible for fatty acid and triglyceride synthesis, while stimulating the expression of the genes involved in fatty acid oxidation and thermogenesis. PUFA induce fatty acid oxidative genes via a ligand-mediated process by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor-α. This dissertation presented evidence to demonstrate that PUFA suppress lipogenic gene transcription by inhibiting sterol regulatory element binding protein-1 (SREBP-1) expression via enhancing its transcript decay.; Supplementing a fat-free, high glucose diet with oils rich in n-6 and n-3 PUFA reduced the hepatic content of membrane precursor and nuclear mature SREBP-1 by 60 and 85% respectively. The PUFA-dependent decrease in nuclear content of mature SREBP-1 was paralleled by a 70–90% suppression in fatty acid synthase gene transcription. In contrast, dietary monounsaturated fatty acid, 18:1(n-9), had no inhibitory influence on the expression of SREBP-1 or fatty acid synthase. PUFA reduction of SREBP-1 protein was paralleled by a reduction of SREBP-1 mRNA abundance. Nuclear run-on assays revealed that PUFA-dependent inhibition of SREBP-1 gene expression was at a posttranscriptional level. When rat hepatocytes in monolayer culture were treated with albumin-bound 20:4(n-6) or 20:5(n-3), the half-life of SREBP-1c and 1a was reduced from 10.0 h to 4.6 h and 11.6 h to 7.6 h, respectively. Thus PUFA accelerated the degradation of SREBP-1 transcripts and the decay of SREBP-1c transcript was more sensitive to PUFA than was SREBP-1a. Translation inhibition assays revealed that the decay of SREBP-1 transcripts was coupled with translation, suggesting the involvement of de novo synthesized decay factors or the involvement of ribosomes. 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 the characteristic of a destabilizing element.