High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production.
Treatments with high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may induce the expression of sterol regulatory element binding protein (SREBP)-target genes, causing different effects from those attributed to the reduction of hepatic cholesterol content. The aim of this study was to investigate the effects of high doses of statins on the key enzymes involved in VLDL production in normolipidemic rats. To examine whether the effects caused by statin treatment are a consequence of HMG-CoA reductase inhibition, we tested the effect of atorvastatin on these enzymes in mevalonate-fed rats. Atorvastatin and simvastatin enhanced not only HMG-CoA reductase but also the expression of the SREBP-2 gene itself. As a result of the overexpression of SREBP-2 caused by the statin treatment, genes regulated basically by SREBP-1, as FA synthase and acetyl-coenzyme A carboxylase, were also induced and their mRNA levels increased. DAG acyltransferase and microsomal TG transfer protein mRNA levels as well as phosphatidate phosphohydrolase activity were increased by both statins. Simvastatin raised liver cholesterol content, ACAT mRNA levels, and CTP:phosphocholine cytidylyltransferase activity, whereas it reduced liver DAG and phospholipid content. Mevalonate feeding reversed all changes induced by the atorvastatin treatment. These results show that treatment with high doses of statins induces key enzymes controlling rat liver lipid synthesis and VLDL assembly, probably as a result of SREBP-2 overexpression. Despite the induction of the key enzymes involved in VLDL production, both statins markedly reduced plasma TG levels, suggesting that different mechanisms may be involved in the hypotriglyceridemic effect of statins at high or low doses.
Roglans
Núria
N
Departamento Farmacología y Química Terapéutica, Facultad de Farmacia, Núcleo Universitario de Pedralbes, Barcelona, Spain.
Verd
Joan C
JC
Peris
Cristina
C
Alegret
Marta
M
Vázquez
Manuel
M
Adzet
Tomás
T
Díaz
Cristina
C
Hernández
Gonzalo
G
Laguna
Juan C
JC
Sánchez
Rosa M
RM
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000069059:Atorvastatin; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis / Q000097:blood; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010743:Phospholipids / Q000096:biosynthesis; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008079:Lipoproteins, VLDL; D010743:Phospholipids; D011758:Pyrroles; D012333:RNA, Messenger; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase