High doses of atorvastatin and simvastatin induce key enzymes involved in VLDL production

Autor: Rosa M. Sánchez, Tomás Adzet, Núria Roglans, Juan C. Laguna, Marta Alegret, Cristina Díaz, Cristina Peris, Manuel Vázquez, Gonzalo Hernández, Joan C Verd
Rok vydání: 2002
Předmět:
Male
Simvastatin
medicine.medical_specialty
Very low-density lipoprotein
Atorvastatin
Lipoproteins
VLDL
Reductase
Biology
Biochemistry
Rats
Sprague-Dawley
Cricetinae
Internal medicine
medicine
Animals
Pyrroles
RNA
Messenger
Phospholipids
Triglycerides
chemistry.chemical_classification
Mesocricetus
Anticholesteremic Agents
Fatty Acids
Organic Chemistry
nutritional and metabolic diseases
Cell Biology
Rats
Sterol regulatory element-binding protein
DNA-Binding Proteins
Enzyme Activation
Cholesterol
Enzyme
Endocrinology
Liver
chemistry
Heptanoic Acids
Acyltransferase
HMG-CoA reductase
biology.protein
Hydroxymethylglutaryl CoA Reductases
lipids (amino acids
peptides
and proteins)
Fatty Acid Synthases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Acetyl-CoA Carboxylase
Sterol Regulatory Element Binding Protein 2
Transcription Factors
medicine.drug
Zdroj: Scopus-Elsevier
ISSN: 1558-9307
0024-4201
DOI: 10.1007/s11745-002-0916-0
Popis: 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.
Databáze: OpenAIRE
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