BACKGROUND: Qualitative dynamics of small gene regulatory networks have been studied in quite some details both with synchronous and asynchronous analysis. However, both methods have their drawbacks: synchronous analysis leads to spurious attractors and asynchronous analysis lacks computational efficiency, which is a problem to simulate large networks. We addressed this question through the analysis of a major biosynthesis pathway. Indeed the cholesterol synthesis pathway plays a pivotal role in dislypidemia and, ultimately, in cancer through intermediates such as mevalonate, farnesyl pyrophosphate and geranyl geranyl pyrophosphate, but no dynamic model of this pathway has been proposed until now. RESULTS: We set up a computational framework to dynamically analyze large biological networks. This framework associates a classical and computationally efficient synchronous Boolean analysis with a newly introduced method based on Markov chains, which identifies spurious cycles among the results of the synchronous simulation. Based on this method, we present here the results of the analysis of the cholesterol biosynthesis pathway and its physiological regulation by the Sterol Response Element Binding Proteins (SREBPs), as well as the modeling of the action of statins, inhibitor drugs, on this pathway. The in silico experiments show the blockade of the cholesterol endogenous synthesis by statins and its regulation by SREPBs, in full agreement with the known biochemical features of the pathway. CONCLUSION: We believe that the method described here to identify spurious cycles opens new routes to compute large and biologically relevant models, thanks to the computational efficiency of synchronous simulation. Furthermore, to the best of our knowledge, we present here the first dynamic systems biology model of the human cholesterol pathway and several of its key regulatory control elements, hoping it would provide a good basis to perform in silico experiments and confront the resulting properties with published and experimental data. The model of the cholesterol pathway and its regulation, along with Boolean formulae used for simulation are available on our web site http://Bioinformaticsu613.free.fr. Graphical results of the simulation are also shown online. The SBML model is available in the BioModels database http://www.ebi.ac.uk/biomodels/ with submission ID: MODEL0568648427. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-24T13:35:08Z 2016-01-23T07:51:39Z

<div><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px;"><font face="Georgia" size="2">Acetoacetyl CoA</font></span></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">25</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">40</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">N</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">7</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">18</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">3</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">S   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> 851.607486 </span></font></div><font face="Georgia" size="2"><span style="line-height: 19px; background-color: rgb(255, 255, 255);">PubChem ID: </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=92153[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">92153</font></a></font>

2015-11-15T18:15:59Z

<div><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255); margin-left: 0px !important;"><font face="Georgia" style="font-size: 14px; line-height: 19px; white-space: normal;">HMGCR ? 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens]</font></dt></div><div><font face="Georgia"></font><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Gene ID:</dt><span style="font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);"> </span><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);">3156</dd></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">geranyl diphosphate</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">10</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">20</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">7</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">2</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 314.209124</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=445995[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">445995</font></a></font></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">isopentenyl pyrophosphate</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">5</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">12</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">7</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">2</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 246.092104</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><font><span style="line-height: 19px; background-color: rgb(255, 255, 255);">1195</span></font></font></div>

2015-11-15T18:15:59Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Lanosterol 14-alpha demethylase</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q16850</span></font></div>

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<font face="Georgia">Transcripts of either of the t<span style="font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);">wo genes to produce the two HMG synthase proteins which function in the mitochondria or cytoplasm:</span></font><div><div style="font-size: 12.222222328186035px; line-height: 15px; background-color: rgb(255, 255, 255);"><ul style="list-style-type: square; line-height: 1.5em; list-style-image: url(data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAUAAAANCAMAAABW4lS6AAAAGXRFWHRTb2Z0d2FyZQBBZG9iZSBJbWFnZVJlYWR5ccllPAAAAAZQTFRFAFKM////QIUK9QAAAAJ0Uk5T/wDltzBKAAAAGklEQVR42mJgBAEGokgGBjBGBxBxsBqAAAMACHwALd5r8ygAAAAASUVORK5CYII=); margin: 0.3em 0px 0px 1.5em; padding: 0px;"><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="font-size: 14px; line-height: 19px;">HMGCS2</span><span style="font-size: 14px; line-height: 19px;"> </span><span style="font-size: 10pt;">? 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) [Homo sapiens], </span><span style="font-size: 10pt;">Gene </span></font><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; margin-left: 0px !important;">ID:</dt><span style="font-size: 12px; line-height: 16.796875px;"> </span><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px;">3158</dd></li><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="font-size: 14px; line-height: 19px;">HMGCS1</span><span style="font-size: 14px; line-height: 19px;"> ? 3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble) [Homo sapiens], </span><span style="font-size: 10pt;">Gene </span></font><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; margin-left: 0px !important;">ID:</dt><span style="font-size: 12px; line-height: 16.796875px;"> </span><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px;">3157</dd></li></ul></div></div>

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\r\n \r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">A family of drugs that are HMG-CoA reductase inhibitors that lower cholesterol by inhibiting the enzyme\r\nHMG-CoA reductase, which is rate-limiting in the cholesterol synthesis pathway [1]. A potent example of a statin is:</font></p><p><ul><li><span style="font-family: Georgia; font-size: small; border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Lovastatin, </span><span style="font-family: Georgia; font-size: small; border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="font-family: Georgia; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">24</sub><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="font-family: Georgia; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">37</sub><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);">NaO</span><sub style="font-family: Georgia; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">6</sub><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);">   </span><span style="font-family: Georgia; font-size: small; border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);"> 444.536749, </span><span style="font-family: Georgia; font-size: small; line-height: 17px; background-color: rgb(255, 255, 255);">PubChem ID: </span><span style="font-family: Georgia; font-size: small; line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><span style="font-family: Georgia; font-size: small; line-height: 19px; background-color: rgb(255, 255, 255);">16760544</span></li></ul></p>\r\n </div>\r\n </div>\r\n </div>

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<div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Can exist in the mitochondria or in the cytosol. </font></span></div><font face="Georgia" size="2"></font><ul><li><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Acetyl-CoA acetyltransferase, cytosolic (Homo sapiens), </span><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID:</span><span style="background-color: rgb(255, 255, 255);">Q9BWD1</span></li><li><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Acetyl-CoA acetyltransferase, mitochondrial (Homo sapiens), </span><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P24752</span></li></ul>

2015-11-15T18:15:59Z

<font face="Georgia" size="2">Complex of proteins containing Insig1, SREBP (</font><span style="font-family: Georgia; font-size: small;">mostly SREBP2 but to a lesser degree SREBP1</span><font face="Georgia" size="2">) and SCAP:</font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Insulin-induced gene 1 protein (<em>Homo sapiens</em>), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">O15503</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein (<em>Homo sapiens</em>), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P36956 </span></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 16px;">Sterol regulatory element-binding protein 2 (</span><i style="font-family: Georgia; font-size: small; line-height: 15.989583969116211px;">Homo sapiens)</i><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 16px;">, UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12772</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein cleavage-activating protein (</span><i style="font-family: Georgia; font-size: small; line-height: 15.989583969116211px;">Homo sapiens)</i><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">, UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12770</span></li></ul></div>

2015-11-15T18:15:59Z

<font face="Georgia" size="2">Can occur in the mitochondria or in the cytoplasm:</font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Hydroxymethylglutaryl-CoA synthase, mitochondrial (<em>Homo sapiens</em>), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P54868</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Hydroxymethylglutaryl-CoA synthase, cytoplasmic (<em>Homo sapiens</em>), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q01581</span></li></ul></div>

2015-11-15T18:15:59Z

<font size="2" face="Georgia">Complex of SREBP (mostly SREBP2 but to a lesser degree SREBP1) and SCAP:</font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 1(Homo sapiens), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P36956</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 2 (Homo sapines), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12772</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein cleavage-activating protein (Homo sapiens), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12770</span></li></ul></div>

2015-11-15T18:15:59Z

<h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px; line-height: 1.5; background-color: rgb(255, 255, 255);"><span style="font-weight: normal;"><font face="Georgia" size="2"><span class="gn">CYP51A1</span> cytochrome P450, family 51, subfamily A, polypeptide 1 [ <em class="tax">Homo sapiens</em> (human) ], </font></span><span style="font-family: Georgia; font-size: small; font-weight: normal; line-height: 17px;">Gene ID: 1595</span></h1>

2015-11-15T18:15:59Z

<font face="Georgia">SREBP (mostly SREBP2 but to a lesser degree SREBP1)</font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 1 (Homo sapiens), UniProt ID:</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P36956</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 2 (Homo sapiens), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12772</span></li></ul></div>

2015-11-15T18:15:59Z

<font face="Georgia">Important biological molecule and precursor to vitamins and steroids. </font><div><font face="Georgia">PubChem ID:<a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=5997[uid]" style="border: 0px; outline: 0px; font-size: 14px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">5997</font></a></font></div>

2015-11-15T18:15:59Z

<font face="Georgia" size="2">Precursor to SREBP (mostly SREBP2 but to a lesser degree SREBP1)</font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 1 (Homo sapiens), UniProt ID:</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P36956</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Sterol regulatory element-binding protein 2 (Homo sapiens), UniProt ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Q12772</span></li></ul></div>

2015-11-15T18:15:59Z

<div><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px;"><font face="Georgia" size="2">Desmosterol</font></span></span></div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">27</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">44</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">O   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> 384.63766</span></font><div><font face="Georgia" size="2"><span style="line-height: 17px; background-color: rgb(255, 255, 255);">PubChem ID: </span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=439577[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">439577</font></a></font></div>

2015-11-15T18:15:59Z

<div style="line-height: normal;"><span style="line-height: 16.796875px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">RNA transcript from either </font></span></div><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16.78819465637207px;">Mitochondrial: </span><span class="gn" style="font-family: Georgia; font-size: small; line-height: 1.5;">ACAT1</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">acetyl-CoA acetyltransferase 1 [</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><em class="tax" style="font-family: Georgia; font-size: small; line-height: 1.5;">Homo sapiens</em><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">(human) ], </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 17px;">Gene ID: 38</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16.78819465637207px;">Cytosolic: </span><span class="gn" style="font-family: Georgia; font-size: small; line-height: 1.5;">ACAT2</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">acetyl-CoA acetyltransferase 2 [</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><em class="tax" style="font-family: Georgia; font-size: small; line-height: 1.5;">Homo sapiens</em><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">(human) ], </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 17px;">Gene ID: 39</span></li></ul></div>

2015-11-15T18:15:59Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Farnesyl pyrophosphate synthase</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P14324</span></font></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">3-hydroxy-3-methylglutaryl-coenzyme A</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">27</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">44</sub><span style="line-height: 17px;">N</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">7</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">20</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">3</sub><span style="line-height: 17px;">S   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 911.659446</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=445127[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">44512</font></a></font></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mevalonic Acid</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">6</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">12</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">4</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 148.15708</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">439230</span></font></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">3,3-dimethylallyl pyrophosphate</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">5</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">12</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">7</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">2</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 246.092104</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=647[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">647</font></a></font></div>

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<font face="Georgia">Transcript of:</font><div style="font-family: Arial, Verdana;"><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px; font-weight: normal; background-image: none; background-attachment: scroll; background-color: rgb(255, 255, 255); border-bottom-width: 1px; border-bottom-style: solid; border-bottom-color: rgb(170, 170, 170); overflow: hidden; width: auto; font-size: 22.22222328186035px; font-family: Arial, sans-serif; line-height: 1.5; background-position: 0px 0px; background-repeat: repeat repeat;"><font face="Georgia" size="2"><span class="gn">FDPS</span> farnesyl diphosphate synthase [ <em class="tax">Homo sapiens</em> (human) ], </font><span style="font-family: Georgia; font-size: small; line-height: 17px;">Gene ID: 2224</span></h1></div>

2015-11-15T18:15:59Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">3-hydroxy-3-methylglutaryl-coenzyme A reductase</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P04035</span></font></div>

2015-11-15T18:15:59Z

<font face="Georgia" size="2">Transcript of:</font><div><div style="line-height: 15px; background-color: rgb(255, 255, 255);"><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; line-height: 16.796875px; margin-left: 0px !important;"><font face="Georgia" style="line-height: 19px; white-space: normal;" size="2">HMGCR ? 3-hydroxy-3-methylglutaryl-CoA reductase [Homo sapiens]</font></dt></div><div style="line-height: 15px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"></font><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; line-height: 16.796875px; margin-left: 0px !important;">Gene ID:</dt><span style="line-height: 16.796875px;"> </span><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap; line-height: 16.796875px;">3156</dd></div></div>

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<div><font face="Georgia"><span style="font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);">Two genes to produce the two HMG synthase proteins which function in the mitochondria or cytoplasm:</span></font></div><div><ul><li><span style="font-family: Georgia; font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);">HMGCS2</span><span style="font-family: Georgia; font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);"> </span><span style="font-family: Georgia; font-size: 10pt;">? 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) [Homo sapiens], </span><span style="font-size: 10pt; font-family: Georgia;">Gene </span><dt style="font-family: Georgia; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">ID:</dt><span style="font-family: Georgia; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);"> </span><dd style="font-family: Georgia; margin: 0px; display: inline; padding: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);">3158</dd></li><li><span style="font-family: Georgia; font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);">HMGCS1</span><span style="font-family: Georgia; font-size: 14px; line-height: 19px; background-color: rgb(255, 255, 255);"> ? 3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble) [Homo sapiens], </span><span style="font-size: 10pt; font-family: Georgia;">Gene </span><dt style="font-family: Georgia; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">ID:</dt><span style="font-family: Georgia; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);"> </span><dd style="font-family: Georgia; margin: 0px; display: inline; padding: 0px; white-space: nowrap; font-size: 12px; line-height: 16.796875px; background-color: rgb(255, 255, 255);">3157</dd></li></ul></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">5-diphosphomevalonic acid</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">6</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">14</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">10</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">2</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 308.116884</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">439418</span></font></div>

2015-11-15T18:15:59Z

<div><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px;"><font face="Georgia" size="2">Acetyl Coenzyme A</font></span></span></div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">23</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">38</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">N</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">7</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">17</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">3</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">S   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> 809.570806 </span></font><div><font face="Georgia" size="2"><span style="line-height: 17px; background-color: rgb(255, 255, 255);">PubChem ID: </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=444493[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">444493</font></a></font></div>

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Transcript of <div><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px; font-weight: normal; background-image: none; background-attachment: scroll; background-color: rgb(255, 255, 255); border-bottom-width: 1px; border-bottom-style: solid; border-bottom-color: rgb(170, 170, 170); overflow: hidden; width: auto; font-size: 22.22222328186035px; font-family: Arial, sans-serif; line-height: 1.5; background-position: 0px 0px; background-repeat: repeat repeat;"><font face="Georgia" size="2"><span class="gn">CYP51A1</span> cytochrome P450, family 51, subfamily A, polypeptide 1 [ <em class="tax">Homo sapiens</em> (human) ], </font><span style="font-family: Georgia; font-size: small; line-height: 17px;">Gene ID: 1595</span></h1></div>

2015-11-15T18:15:59Z

<span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">farnesyl pyrophosphate</font></span><div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="line-height: 17px;"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">15</sub><span style="line-height: 17px;">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">28</sub><span style="line-height: 17px;">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">7</sub><span style="line-height: 17px;">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">2</sub><span style="line-height: 17px;">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="line-height: 17px;"> 382.326144</span></font></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID: </span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=445713[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);"><font color="#000000">445713</font></a></font></div>

2015-11-15T18:15:59Z

<font face="Georgia" size="2" style="font-style: normal; font-variant: normal; line-height: normal;">Gene that transcribes acetyl coenzyme A transferase. There are two forms of acetyl coenzyme A transferase, mitochondrial and cytosolic. </font><div><ul><li><font face="Georgia" size="2">Mitochondrial: </font><span class="gn" style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">ACAT1</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">acetyl-CoA acetyltransferase 1 [</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><em class="tax" style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">Homo sapiens</em><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> (human) ], </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 17px;">Gene ID: 38</span></li><li><span style="line-height: 17px;"><font face="Georgia" size="2">Cytosolic: </font></span><span class="gn" style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">ACAT2</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">acetyl-CoA acetyltransferase 2 [</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><em class="tax" style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">Homo sapiens</em><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;"> </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 1.5;">(human) ], </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 17px;">Gene ID: 39</span></li></ul></div>

2015-11-15T18:15:59Z

<h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px; line-height: 1.5; background-color: rgb(255, 255, 255);"><span style="font-weight: normal;"><font face="Georgia" size="2"><span class="gn">FDPS</span> farnesyl diphosphate synthase [ <em class="tax">Homo sapiens</em> (human) ], </font></span><span style="font-family: Georgia; font-size: small; line-height: 17px; font-weight: normal;">Gene ID: 2224</span></h1>

2015-11-15T18:15:59Z

Acetyl CoA and acteyl CoA acetyltransferase activate Acetoacetyl CoA [1]. 

<font face="Georgia">Catalyzes the reaction of acetyl CoA into acetoacetyl CoA [1]. Acetyl CoA acetyltransferase activates acetoacetyl coA [1,2,3,4]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Acetyl-CoA combines with itself to give acetoacetyl-CoA [1]. Acetyl CoA, therefore activates acetoacetyl CoA [1,2,3,4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_29 1 S_8 1

<font face="Georgia">Mature SREBP activates HMG CoA reductase gene [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Once SREBP is matured, it migrates to the nucleus\r\nand acts as a transcription factor upon binding to sterol\r\nregulatory elements (SRE) to activate the genes coding for\r\nthe main enzymes of the HMG-CoA reductase pathway; this activates the HMG-CoA synthase gene [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_13 1

<font face="Georgia">Dimethyl allyl pyrophosphate and isopentenyl pyrophosphate activate geranyl pyrophosphate [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Active isopentenyl pyrophosphate combines with its own product (dimethyl allyl pyrophosphate) to form active geranyl pyrophosphate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Active isopentenyl pyrophosphate combines with its own product (dimethyl allyl pyrophosphate) to\r\nform active geranyl pyrophosphate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_4 1 S_21 1

<font face="Georgia">Mevalonyl pyrophosphate actives isopentenyl pyrophosphate [1].</font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Active mevalonyl pyrophosphate transforms into active isopentenyl pyrophosphate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_28 1

<font face="Georgia">The cyp 51 mRNA activates the cyp 51 protein [1].</font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Translation of the Cyp 51 mRNA produces an active protein [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_30 1

<font face="Georgia">HMG synthase gene activates HMG CoA synthase RNA [1]. </font>

<font face="Georgia">Transcription of the HMG CoA synthase gene produces an active transcript [1, 2, 3, 4].</font>

S_27 1

<span style="font-family: Georgia;">Statins activate themselves in this model [1].</span>

<font face="Georgia">Statins activate themselves in this model [1].</font>

S_7 1

<h3 style="margin: 0px; padding: 0.5em 0px 0.17em; background-image: none; background-attachment: scroll; border-bottom-width: medium; border-bottom-style: none; overflow: hidden; width: auto; background-position: 0px 0px;"><font size="2">Acetyl_CoA_acetyltransferase_RNA positively regulates Acetyl_CoA_acetyltransferase [1, 2, 3, 4]</font></h3><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="font-size: 12px;"><br/></span></div>

<font face="Georgia">Translation of the acetyl coA acetyltransferase mRNA produces an active acetyl CoA acteyltransferase [1, 2, 3, 4].</font>

S_17 1

<font face="Georgia">Cholesterol is a negative regulator of Insig SREBP-SCAP [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Giovanni" size="2">When the cholesterol level is low,\r\nInsig1 interaction with SREBP-SCAP complex is relieved. Cholesterol catalyzes the degradation of insig from the SREBP-SCAP complex [1, 2, 3, 4]. </font></p>\r\n </div>\r\n </div>\r\n </div>

S_14 1

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">HMG CoA synthase RNA activates HMG CoA synthase [1]. </span>

<br class="Apple-interchange-newline"/><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Translation of the HMG CoA synthase mRNA produces an active protein [1, 2, 3, 4].</span>

S_6 1

<font face="Georgia">Insig SREBP-SCAP activates SREBP-SCAP; statins inactivate SREBP-SCAP and dominate over insig SREBP-SCAP [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column"><p><span style="font-family: Giovanni; font-size: 10pt;">Dissociation from Insig creates the active </span><span style="font-size: 10.000000pt; font-family: 'Giovanni'">SREBP-SCAP\r\ncomplex [1,2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia">Statins inactivate SREBP-SCAP [1, 2, 3, 4]. </font>

S_9 1 S_7 1

<font face="Georgia">Mature SREBP activates the cyp 51 gene [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Once SREBP is matured, it migrates to the nucleus\r\nand acts as a transcription factor upon binding to sterol\r\nregulatory elements (SRE) to activate the genes coding for\r\nthe main enzymes of the HMG-CoA reductase pathway; this activates the CYP51 gene [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_13 1

<font face="Georgia">Premature SREBP activates mature SREBP [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Matured SREBP, called mSREBP, is\r\nautomatically derived and activated from pSREBP [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_15 1

<font face="Georgia">Desmosterol or sepdehydrocholesterol activate cholesterol [1].</font>

<span style="font-family: Giovanni;">Through several transformations </span><span style="font-family: Giovanni;">desmosterol </span><span style="font-family: Giovanni;">produces active </span><span style="font-family: Giovanni;">cholesterol</span><span style="font-family: Giovanni;">[1, 2, 3, 4]. </span>

<span style="color: rgb(79, 79, 79); font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-family: Giovanni;">Through several transfomations </span><span style="color: rgb(79, 79, 79); font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-family: Giovanni;">7-dehydrocholesterol </span><span style="color: rgb(79, 79, 79); font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-family: Giovanni;">produces active </span><span style="color: rgb(79, 79, 79); font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-family: Giovanni;">cholesterol</span><span style="color: rgb(79, 79, 79); font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-family: Giovanni;">[1, 2, 3, 4]. </span>

S_16 1 S_23 1

<font face="Georgia">SREBP SCAP activates premature SREBP [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">SREBP-SCAP to migrate to the Golgi apparatus\r\nwhere SREBP is cleaved by two proteases called S1P and\r\nS2P. This activates premature SREBP. A</span><span style="font-family: Giovanni; font-size: 10pt;"> non-fully\r\nmatured SREBP protein, called here pSREBP (for precursor-SREBP) is automatically produced if SREBP-SCAP is\r\npresent [1, 2, 3, 4].</span></p>\r\n \r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'"> <br/></span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_11 1

<font face="Georgia">Lanosterol activates desmosterol [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Through several transformations, lanosterol produces active desmosterol [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_25 1

<font face="Georgia">Acetyl CoA acetyltransferase gene activates its mRNA product [1].</font>

<font face="Georgia">Transcription of this gene produces an active RNA transcript [1, 2, 3, 4].</font>

S_33 1

<font face="Georgia">FPP synthase RNA activates FPP synthase [1] </font>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Translation of the FPP synthase mRNA produces active FPP synthase [1, 2, 3, 4].</span>

S_22 1

<font face="Georgia">Acetoacetyl CoA activates HMG CoA when acetyl CoA and HMG CoA synthase are active [1]. </font>

S_1 1 S_29 1 S_10 1

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">HMG-CoA reductase and HMG-CoA activates mevalonic acid [1]. </span>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">In the presence of HMG-CoA reductase, HMG-CoA will\r\nproduce mevalonic acid [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">In the presence of HMG-CoA reductase, HMG-CoA will produce mevalonic acid [1, 2, 3, 4].</span>

S_19 1 S_24 1

<font face="Georgia">Isopentenyl pyrophosphate activates dimethyl allylpyrophosphate [1].</font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Active isopentenyl pyrophosphate gives active dimethyl allyl pyrophosphate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_4 1

<font face="Georgia">FPP synthase gene activates FPP synthase RNA [1]. </font>

<font face="Georgia">Transcription of the FPP synthase gene produces an active transcript [1, 2, 3, 4].</font>

S_34 1

<font face="Georgia">Lanosterol activates septdehydrocholesterol [1]. </font>

<span style="font-family: Giovanni;">Through several transformations, lanosterol produces active septdehydrocholesterol [1, 2, 3, 4]. </span>

S_25 1

<font face="Georgia">HMG CoA reductase RNA activates HMG CoA reductase; statins deactivates HMG CoA reductase and is dominant over HMG CoA reductase RNA [1]. </font>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Translation of the HMG CoA reductase mRNA produces an active protein [1, 2, 3, 4].</span>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column"><p><span style="font-family: Giovanni; font-size: 10pt;">Active statins </span><span style="font-size: 10.000000pt; font-family: 'Giovanni'">blockade HMG-\r\nCoA reductase and deactivate it [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_26 1 S_7 1

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Squalene actives lanosterol [1].</span>

S_32 1

<font face="Georgia">HMG CoA reductase gene activates HMG CoA reductase [1]. </font>

<font face="Georgia">Transcription of the HMG CoA reductase gene produces an active mRNA [1, 2, 3, 4].</font>

S_2 1

<font face="Georgia">Mature SREBP activates HMG CoA synthase gene [4]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Once SREBP is matured, it migrates to the nucleus\r\nand acts as a transcription factor upon binding to sterol\r\nregulatory elements (SRE) to activate the genes coding for\r\nthe main enzymes of the HMG-CoA reductase pathway; this activates the HMG-CoA synthase gene [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_13 1

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Mevalonic acid activates mevalonyl pyrophosphate [1].</span>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">ATP is also considered to be\r\npresent in sufficient amounts, so that mevalonic acid will\r\ntransform into mevalonyl pyrophosphate [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_20 1

Acetyl CoA activates itself [1].

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Acetyl-CoA which can, in this model, be either\r\npresent, or absent in case of deficiency. Acetyl-CoA combines with itself to activate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_29 1

<font face="Georgia">The CYP 51 gene activates CYP 51 mRNA [1].</font>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Transcription of the CYP51 gene produces an active CYP 51 mRNA [1, 2, 3, 4].</span>

S_12 1

<font face="Georgia">Farnesyl pyrophosphate is activated when geranyl pyrophosphate is active and not FPP synthase [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Active geranyl pyrophosphate combines with isopentenyl pyrophosphate to give active farnesyl pyrophosphate [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">FPP Synthase inhibits the reaction of geranyl pyrophosphate and isopentenyl pyrophosphate [1, 2, 3, 4].</span>

S_3 1 S_18 1

<span style="color: rgb(79, 79, 79); font-family: Giovanni; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Farnesyl pyrophosphate activates squaline [1]. </span>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Active farnesyl pyrophosphate will lose two inorganic phosphates and one H+ ion to give presqualene\r\npyrophosphate that will get two hydrogens from NADPH\r\nand H+ and lose two more inorganic phosphates to transform into active squalene [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_31 1

<font face="Georgia">Mature SREBP activates the acetyl CoA acetyltransferase gene [1].</font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Once SREBP is matured, it migrates to the nucleus\r\nand acts as a transcription factor upon binding to sterol\r\nregulatory elements (SRE) to activate the genes coding for\r\nthe main enzymes of the HMG-CoA reductase pathway; this activates the Acetyl CoA acetyl transferase gene [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>

S_13 1

<font face="Georgia">Mature SREBP activates FPP synthase gene [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Giovanni'">Once SREBP is matured, it migrates to the nucleus\r\nand acts as a transcription factor upon binding to sterol\r\nregulatory elements (SRE) to activate the genes coding for\r\nthe main enzymes of the HMG-CoA reductase pathway; this activates the FPP synthase gene [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>

S_13 1