Inhibition of Cholesterol Biosynthesis in Hypercholesterolemia
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J Med Biochem 2013; 32 (1) DOI: 10.2478/v10011-012-0020-3 UDK 577.1 : 61 ISSN 1452-8258 J Med Biochem 32: 16–19, 2013 Review article Pregledni ~lanak INHIBITION OF CHOLESTEROL BIOSYNTHESIS IN HYPERCHOLESTEROLEMIA – IS IT THE RIGHT CHOICE? INHIBICIJA BIOSINTEZE HOLESTEROLA U HIPERHOLESTEROLEMIJI – DA LI JE PRAVI IZBOR? Abdurrahman Coskun, Mustafa Serteser, Ibrahim Unsal Acibadem University, School of Medicine, Department of Biochemistry, Istanbul, Turkey Summary: Cholesterol biosynthesis is a complex pathway Kratak sadr`aj: Biosinteza holesterola je kompleksan me - comprising more than 20 biochemical reactions. Although ta boli~ki put koji obuhvata vi{e od 20 biohemijskih reakcija. the final product created in the pathway is cholesterol, the Iako je kona~an proizvod koji nastaje holesterol, interme- intermediate products, such as ubiquinone and dolichol, also dijerni proizvodi, kao {to su ubihinon i dolihol, tako|e obez- provide vital metabolic functions. Statins are HGM-CoA be |u ju vitalne metaboli~ke funkcije. Statini su inhibitori reductase inhibitors that stop the production of cholesterol HMG-KoA reduktaze koji zaustavljaju produkciju holestero- by directly inhibiting the mevalonate production. Mevalonate la di rektnom inhibicijom produkcije mevalonata. Mevalonat is a precursor of two additional vital molecules, squalene and je prekursor dva dodatna vitalna molekula, skvalena i ubihi - ubiquinone (coenzyme Q10). We hypothesized that inhibit- no na (koenzim Q10). Postavili smo hipotezu da produ`eno ing the cholesterol biosynthesis with statins for an extended trajanje inhibicije biosinteze holesterola statinima mo`e da duration may potentiate the oxidative stress, neurodegener- po tencira oksidativni stres, neurodegenerativne bolesti i ative disease and cancer. Our recommendation was to meas- kan cer. Tako|e preporu~ujemo odre|ivanje mi{i}nih enzi- ure muscle enzymes, antioxidant capacity, and ubiquinone to ma, antioksidativnog kapaciteta i ubihinona u pra}enju pa- monitor patients receiving the statins for prolonged periods cijenata koji primaju statine u du`em vremenskom periodu. of time. Klju~ne re~i: holesterol, ubihinon, statini Keywords: cholesterol, ubiquinone, statins Introduction Cholesterol biosynthesis comprises more than 20 enzymatically catalyzed reactions and occurs in Cholesterol is the principal sterol in the human four main stages. In the first stage, acetyl-CoA mole- body and contributes to numerous structural and metabolic functions. Cholesterol is the main compo- cules form a six-carbon molecule called mevalonate. nent of cell membranes and lipoproteins, and is a In the second stage, mevalonate is converted to acti- precursor for steroid hormones, bile acids, and vita- vated isoprene units, which are subsequently (stage min D. Similar to other lipids, cholesterol is obtained 3) polymerized to form squalene. In the fourth and from food sources. The presence of cholesterol in the final stage, cyclization of squalene forms the steroid human body is essential. Virtually all tissues, but nucleus and an additional series of changes leads to mainly the liver, adrenal cortex, guts, and reproduc- formation of cholesterol (1, 2). tive tissues, synthesize cholesterol. The first-stage reaction is clinically relevant, as it the target of certain anti-hyperlipidemia drugs. In the first step, two acetyl-CoA molecules condense to form Address for correspondence: acetoacetyl-CoA. Subsequently, a third acetyl-CoA Abdurrahman Coskun, MD con denses with the acetoacetyl-CoA to yield 3-hy- Acibadem Labmed Clinical Laboratories, Altunizade Mah, F.K. Gokay Cad, No: 49, Uskudar, Istanbul, Turkey droxyl 3-methylglutaryl CoA (HMG-CoA). HMG-CoA Phone: +90 532 744 66 83 is then converted to mevalonate by HMG-CoA reduc- e-mail: Coskun2002ªgmail.com tase. Conversion of HMG-CoA to mevalonate is the J Med Biochem 2013; 32 (1) 17 rate-limiting step in the cholesterol biosynthesis, and electrons from FMNH2, which is produced by NADH the primary statin target. dehydrogenase (complex I), and from FADH2, which is produced by succinate dehydrogenase (complex II) In the second stage, mevalonate is converted to and acyl CoA dehydrogenase. These steps are isopentenyl pyrophosphate (IPP). IPP units condense absolutely required for subsequent electron transfer to form geranyl pyrophosphate (GPP) and then far- to complex III. Ubiquinones carry both electrons and nesyl pyrophosphate (FPP). In addition to cholesterol protons and play a central role in coupling the elec- bio synthesis, the isoprene products perform many tron flow to proton movement, which is essential for vital functions discussed in more details herein. oxidative phosphorylation. A decreased ubiquinone Despite its numerous beneficial structural and level results in decreased electron transport and sub- metabolic functions, elevated cholesterol levels are a sequently decreased ATP production. Although significant risk factor of coronary artery disease. Thus, ubiquinones are concentrated in the inner mitochon- inhibiting the cholesterol biosynthesis is widely drial membrane, they are also widely distributed in accepted as a method for treating the hypercholes- other cellular membranes (4) and perform several cell terolemia, and numerous drugs have been developed metabolism functions other than ATP production, to inhibit the enzymes at different steps during choles- including the cell signalling and gene expression (5). terol biosynthesis. Oxidative stress causes DNA and protein damage, and plays an important role in the development of cancer, neurodegenerative diseases, cardiovascular Inhibition of Cholesterol Biosynthesis disorders, and aging (6, 7). According to the oxida- by Statins tive stress theory, atherosclerosis is the result of the oxidative modification of low-density lipoproteins Statins comprise a group of drugs (simvastatin, (LDL) by reactive oxygen species (ROS) in the arterial lovastatin, mevastatin, atorvastatin, pravastatin) that wall. ROS induce the oxidation of LDL, whose uptake inhibit cholesterol biosynthesis. These drugs selective- by macrophages is easier than uptake of non-oxidized ly inhibit the rate-limiting enzyme of the cholesterol LDL. Oxidative stress, together with the weakened biosynthesis, HGM-CoA reductase, thereby, lowering anti oxidative defense system, induces the vascular the blood cholesterol levels. However, statins do not dys function and promotes atherosclerosis. Ubiquino - inhibit the enzyme completely. They inhibit roughly ne inhibits atherosclerosis development as described 45% to 95% of HGM-CoA reductase activity depend- by the oxidative theory (8), and is considered the anti- ing on the dose and the type of statins used (3). risk factor of atherosclerosis. HGM-CoA reductase exerts its effects during the first stage of cholesterol biosynthesis, and thus inhibition It has been shown that statin therapy decreases of HGM-CoA reductase inhibits all of the metabolical- circulating and muscle ubiquinone levels (8, 9). De- ly active intermediate molecules produced during the crea sed levels of ubiquinone may be responsible for stages 2–4 of the cholesterol biosynthesis pathway. such statin side effects as myotoxicity and rhabdomyol- ysis (10). Although it is not still clear, some study results indicate that decreased levels of ubiquinone during Hypothesis statin therapy might be associated with the subclinical cardiomyopathy and that this situation is reversible with We hypothesized that HGM-CoA reductase is not the ubiquinone supplementation (11). the most appropriate inhibitory target for lowering the Oxidative stress and mitochondrial dysfunction blood cholesterol levels, particularly for an extended have been implicated in many neurodegenerative dis- duration. Doing so in a large population which meets orders including the Alzheimer’s disease, amyotroph- the criteria for hypercholesterolemia may trigger seri- ic lateral sclerosis, and Parkinson’s disease. For exam- ous diseases in many otherwise healthy individuals. ple, studies suggest that, in Parkinson’s disease, there Cholesterol synthesis is a multi-step reaction, is a deficiency of the complex I activity in the mito- requiring 20 different enzymes to complete the path- chondrial electron transport chain. Interestingly, ubi- way. All of these enzymes catalyze intermediate reac- qui none appears to be a promising agent in the treat- tions and the resulting products accomplish many ment of Parkinson’s disease. Additionally, in animal other metabolic functions. Two of these intermediate models, the experimental studies suggest that ubi- molecules of particular importance are IPP and FPP. quinone protects against many neurodegenerative diseases (12–14). IPP is the precursor of isoprenoids, ubiquinone, and dolichol. Ubiquinone is an essential component In addition to ubiquinone, dolichol metabolism of the electron transport chain, which is located with- and prenylation play important roles in the impact of in the inner mitochondrial membrane and is respon- statins on human metabolism. Dolichol metabolism sible for 95% of all human ATP synthesis reactions. affects glycoprotein and glycolipid synthesis, which Ubiquinone is small and hydrophobic, and thus mo- subsequently enables vital cell cycle functions. Glyco- bile and freely diffusible within the lipid bilayer of the proteins and glycolipids comprise a group of struc- inner mitochondrial membrane. Ubiquinones accept tural and functional proteins of major metabolic 18 Coskun: Inhibition of cholesterol biosynthesis in hypercholesterolemia