Delta5 desaturase mRNA levels are increased by simvastatin via SREBP-1 at early stages, not via PPARalpha, 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 delta5 desaturase activity. To evaluate the delta5 desaturase gene expression and the transcription factors involved, THP-1 cells (a monocytic cell line) were incubated with 5 microM simvastatin for different time periods. The activity of the enzyme, evaluated as product/precursor ratio in the metabolic pathway (starting from [1-(14)C] linoleic acid), increased in treated cells with respect to controls after 24 h, whereas, mRNA levels of the delta5 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 PPARalpha (WY 14643 and fenofibrate) and PPARgamma (ciglitazone) agonists did not affect linoleic acid conversion and the delta5 desaturase activity at any time considered (8-48 h), but they increased the delta5 desaturase mRNA levels, after 48 h; only fenofibrate showed a synergistic effect with simvastatin at this time, with a concomitantly increase in PPARalpha expression and beta-oxidation. Simvastatin alone increased SREBP-1 levels with respect to controls, starting from 8 h of incubation, whereas PPARalpha and linoleic acid beta-oxidation (a PPARalpha 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 delta5 desaturase gene by simvastatin, in THP-1 cells.
Risé
Patrizia
P
Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. patrizia.rise@unimi.it
Ghezzi
Silvia
S
Carissimi
Romina
R
Mastromauro
Francesca
F
Petroni
Anna
A
Galli
Claudio
C
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D000090943:Delta-5 Fatty Acid Desaturase; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D044943:Fatty Acid Desaturases / Q000096:biosynthesis* / Q000235:genetics; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D019821:Simvastatin / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D000924:Anticholesteremic Agents; D000090943:Delta-5 Fatty Acid Desaturase; D047493:PPAR alpha; D047495:PPAR gamma; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D016718:Arachidonic Acid; C006253:pirinixic acid; D002784:Cholesterol; D019787:Linoleic Acid; D019821:Simvastatin; D044943:Fatty Acid Desaturases; D011345:Fenofibrate; C039671:ciglitazone