title: The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase.
abstract: BACKGROUND
  The yeast Saccharomyces cerevisiae can be a useful model for studying cellular mechanisms related to sterol synthesis in humans due to the high similarity of the mevalonate pathway between these organisms. This metabolic pathway plays a key role in multiple cellular processes by synthesizing sterol and nonsterol isoprenoids. Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the cholesterol synthesis pathway. However, the effects of statins extend beyond their cholesterol-lowering action, since inhibition of HMGR decreases the synthesis of all products downstream in the mevalonate pathway. Using transgenic yeast expressing human HMGR or either yeast HMGR isoenzyme we studied the effects of simvastatin, atorvastatin, fluvastatin and rosuvastatin on the cell metabolism.
  
  
  RESULTS
  Statins decreased sterol pools, prominently reducing sterol precursors content while only moderately lowering ergosterol level. Expression of genes encoding enzymes involved in sterol biosynthesis was induced, while genes from nonsterol isoprenoid pathways, such as coenzyme Q and dolichol biosynthesis or protein prenylation, were diversely affected by statin treatment. Statins increased the level of human HMGR protein substantially and only slightly affected the levels of Rer2 and Coq3 proteins involved in non-sterol isoprenoid biosynthesis.
  
  
  CONCLUSIONS
  Statins influence the sterol pool, gene expression and protein levels of enzymes from the sterol and nonsterol isoprenoid biosynthesis branches and this effect depends on the type of statin administered. Our model system is a cheap and convenient tool for characterizing individual statins or screening for novel ones, and could also be helpful in individualized selection of the most efficient HMGR inhibitors leading to the best response and minimizing serious side effects.
authors.forename: Agata
authors.initials: A
authors.lastname: Maciejak
authors.forename: Agata
authors.initials: A
authors.lastname: Leszczynska
authors.forename: Ilona
authors.initials: I
authors.lastname: Warchol
authors.forename: Monika
authors.initials: M
authors.lastname: Gora
authors.forename: Joanna
authors.initials: J
authors.lastname: Kaminska
authors.forename: Danuta
authors.initials: D
authors.lastname: Plochocka
authors.forename: Monika
authors.initials: M
authors.lastname: Wysocka-Kapcinska
authors.forename: Dorota
authors.initials: D
authors.lastname: Tulacz
authors.forename: Joanna
authors.initials: J
authors.lastname: Siedlecka
authors.forename: Ewa
authors.initials: E
authors.lastname: Swiezewska
authors.forename: Maciej
authors.initials: M
authors.lastname: Sojka
authors.forename: Witold
authors.initials: W
authors.lastname: Danikiewicz
authors.forename: Norbert
authors.initials: N
authors.lastname: Odolczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Szkopinska
authors.forename: Grazyna
authors.initials: G
authors.lastname: Sygitowicz
authors.forename: Beata
authors.initials: B
authors.lastname: Burzynska
mesh_terms: D000069059:Atorvastatin; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D000077340:Fluvastatin; D005656:Fungal Proteins / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism*; D030781:Organisms, Genetically Modified; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology; D013261:Sterols / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism
chemical_list: D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D005656:Fungal Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007527:Isoenzymes; D011743:Pyrimidines; D011758:Pyrroles; D013261:Sterols; D013449:Sulfonamides; D013729:Terpenes; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid