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Cholesterol is an essential lipid, available through diet but also synthesized endogenously from acetyl-coenzyme A, formed as a byproduct of glucose and fatty acids through glycolysis and β-oxidation pathways, respectively. Cholesterol is a major end product of the isoprenoid and sterol biosynthetic pathway involving numerous enzymatic steps. Enzymatic defects in the pre-squalene cholesterol synthesis pathway are responsible for inherited sterol disorders such as mevalonic aciduria (MVA) and hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). In the descending post-squalene pathway, enzymatic defects are responsible for disorders such as Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase deficiency (SC4MOL), X-linked dominant chondrodysplasia punctata 2 (CDPX2)/Conradi-Hünermann syndrome, lathosterolosis, desmosterolosis, and the widely known Smith-Lemli-Opitz syndrome (SLOS). Hydrops-ectopic calcification–moth-eaten (HEM)/Greenberg skeletal dysplasia was earlier thought to be a disorder of sterol metabolism but more recently has been shown to be a laminopathy.
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PATHOGENESIS AND EPIDEMIOLOGY
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Cholesterol has numerous essential functions as a major component of cell membranes and myelin in the nervous system, cellular signal transduction and expression (eg, activation of hedgehog proteins), and as a precursor of bile acid and steroid hormone synthesis; thus, it has perhaps a unique influence on both embryonic and postnatal development.
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The isoprenoid synthesis pathway (Fig. 159-1) leads to the synthesis of cholesterol (an important constituent of cell membranes and a precursor of steroid hormones and bile acids), haem A (a component of complex IV of the respiratory chain), ubiquinone (an electron carrier in the respiratory chain), dolichol (which is required for glycosylation of proteins), farnesyl-pyrophosphate, and geranylgeranyl-pyrophosphate (which are important for prenylation of proteins). Prenylation of proteins is important in many signaling cascades in the cell.
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The cholesterol synthesis pathway is tightly regulated. When cholesterol levels in the cell are low, transcription of the HMG-CoA reductase gene (HMGR), and probably the transcription of every other gene involved in the cholesterol synthesis pathway, is upregulated by sterol regulatory element binding proteins, particularly SREBP-2. In ...