Cholesterol biosynthesis localization

Evidence in favor of peroxisomal involvement in cholesterol biosynthesis is the following. The molecular cloning of cDNAs encoding many of these enzymes revealed peroxisomal targeting sequences (W.J. Kovacs, 2003). The availability of specific antibodies allowed immunocytochemical localization to peroxisomes [4] (W.J. Kovacs, 2006). Fibroblasts from individuals with peroxisome biogenesis disorders showed reduced enzymatic activities of cholesterol biosynthetic enzymes, reduced rates of cholesterol synthesis, and lower cholesterol content [4]. Together these data suggest that peroxisomes may play a role in all steps in the cholesterol biosynthetic pathway, except the conversion of famesyl-PP to squalene. The latter reaction is catalyzed by squalene synthase, which is found. solely in the ER. 

Histochemical, cytochemical, developmental, and biochemical studies indicate that much of the brain cholesterol is localized in the lipid-protein layers of the myelin sheath. As a result, this cholesterol is largely removed from the normal metabolic environment of the brain. Thus, although nervous tissue contains relatively large amounts of lipid, biosynthesis and the mean turnover rate of the typical myelin lipids including cholesterol are quite slow. Nevertheless dynamic metabolism may be found in small pools of, for example, cell or organelle membrane, cytoplasmic lipid, or outer parts of the myelin sheath. Such possibilities may serve to explain some of the various anomalous results reported by many workers studying brain cholesterol metabolism. 

Kovacs et al. (2002) reviewed some of the recent findings related to the localization of cholesterol biosynthetic enzymes in peroxisomes and discussed the impairment of cholesterol biosynthesis in peroxisomal deficiency disease. 

In the early stages the intracellular locale of cholesterol biosynthesis shifts back and forth between the cytoplasm and the endoplasmic reticulum but from farnesylpyrophosphate on all steps are... 

Outline of pathways for the biosynthesis of major cellular lipids (other than cholesterol) in a mammalian cell. Most of the metabolism of these lipids occurs on membrane surfaces because of the insoluble nature of the substrates and products. These lipids play three major roles (l) they act as a storehouse of chemical energy, as with triacylglycerols (2) they are structural components of membranes (boxed compounds) and (3) they act as regulatory compounds (underlined), either as eicosanoids, which act as local hormones, or as phosphorylated inositols and diacylglycerols, which function as second messengers. 

Modulation of epidermal hpid biosynthesis has been reported to boost dmg delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum corneum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-dermal delivery of lidocaine or caffeine. Alteration of barrier function was produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-fiirancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (33). 

Cholesterol is formed biosynthetically from isopentenyl pyrophosphate (active isoprene). The majority of cholesterol in the body derives from de novo biosynthesis in the liver [1,2]. Cholesterol synthetic pathway has been assumed to occur primarily in the cytoplasm and endoplasmic reticulum (ER). However, more recent evidences have suggested that the enzymes, except squalene synthase, squalene epoxidase and oxidosqualene cyclase, are partly localized in the peroxisomes, which are essential for normal cholesterol synthesis [11]. 

Attempts have been made to localize the point of ACTH action in corticosteroid biosynthesis, using the postulated sequence as a basis for experimentation. The step, cholesterol— pregnenolone, appears to be... 

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