Background: The yeast Saccharomyces cerevisiae can be a useful model for studying cellular mechanisms related to\r\nsterol synthesis in humans due to the high similarity of the mevalonate pathway between these organisms. This\r\nmetabolic pathway plays a key role in multiple cellular processes by synthesizing sterol and nonsterol isoprenoids.\r\nStatins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the\r\ncholesterol synthesis pathway. However, the effects of statins extend beyond their cholesterol-lowering action, since\r\ninhibition of HMGR decreases the synthesis of all products downstream in the mevalonate pathway. Using\r\ntransgenic yeast expressing human HMGR or either yeast HMGR isoenzyme we studied the effects of simvastatin,\r\natorvastatin, fluvastatin and rosuvastatin on the cell metabolism.\r\nResults: Statins decreased sterol pools, prominently reducing sterol precursors content while only moderately\r\nlowering ergosterol level. Expression of genes encoding enzymes involved in sterol biosynthesis was induced, while\r\ngenes from nonsterol isoprenoid pathways, such as coenzyme Q and dolichol biosynthesis or protein prenylation,\r\nwere diversely affected by statin treatment. Statins increased the level of human HMGR protein substantially and\r\nonly slightly affected the levels of Rer2 and Coq3 proteins involved in non-sterol isoprenoid biosynthesis.\r\nConclusion: Statins influence the sterol pool, gene expression and protein levels of enzymes from the sterol and\r\nnonsterol isoprenoid biosynthesis branches and this effect depends on the type of statin administered. Our model\r\nsystem is a cheap and convenient tool for characterizing individual statins or screening for novel ones, and could\r\nalso be helpful in individualized selection of the most efficient HMGR inhibitors leading to the best response and\r\nminimizing serious side effects.
Loading....