Δ5 desaturase mRNA levels are increased by simvastatin via SREBP-1 at early stages, not via PPARα, in THP-1 cells

In addition to inhibiting cholesterol biosynthesis, statins increase the conversion of linoleic acid to its derivatives, in particular to arachidonic acid, both in vivo and in vitro. Desaturases are the rate-limiting enzymes in this metabolic process and statins markedly enhance Delta 5 desaturase activity. To evaluate the Delta 5 desaturase gene expression and the transcription factors involved, THP-1 cells (a monocytic cell line) were incubated with 5 mu M simvastatin for different time periods. The activity of the enzyme, evaluated as product/precursor ratio in the metabolic pathway (starting from [1-C-14] linoleic acid), increased in treated cells with respect to controls after 24 h, whereas, mRNA levels of the Delta 5 desaturase increased after 12 h of incubation with simvastatin. Fatty acid desaturase genes are regulated by both sterol regulatory element binding proteins (SREBPs) and peroxisome proliferators activated receptors (PPARs). Both PPAR alpha (WY 14643 and fenofibrate) and PPAR gamma (ciglitazone) agonists did not affect linoleic acid conversion and the Delta 5 desaturase activity at any time considered (8-48 h), but they increased the Delta 5 desaturase mRNA levels, after 48 h; only fenofibrate showed a synergistic effect with simvastatin at this time, with a concomitantly increase in PPAR alpha expression and beta-oxidation. Simvastatin alone increased SREBP-1 levels with respect to controls, starting from 8 h of incubation, whereas PPAR alpha and linoleic acid beta-oxidation (a PPAR alpha mediated process) were not affected after 48 h of incubation. These results taken together suggest that SREBP-1 is involved in the early regulation of Delta 5 desaturase gene by simvastatin, in THP-1 cells. (C) 2007 Elsevier B.V. All rights reserved.