Cholesterol de novo

Several tissues of the body are able to synthesize cholesterol de novo (i.e. from its raw materials) the liver is one of these organs. Structurally, cholesterol belongs to the group of compounds called sterols (steroid alcohols) and is derived metabolically from acetate... 

A summary of some of these processes is as follows synthesis of phospholipids and cholesterol de novo synthesis of ribonucleotides synthesis of RNA de novo synthesis of deoxyribonucleotides regulation of synthesis of deoxyribonucleotides salvage pathways duplication of DNA transcription and translation (polypeptide synthesis). After this series of topics, those of fuels and ATP generation, mitosis and, finally, regulation of the cycle, are described and discussed. 

Cells need cholesterol to survive. Cells can either synthesize cholesterol de novo or obtain it from exogenous sources, such as lipoproteins present in the circulation (see Table 14-1 and Rader and Hobbs, 2005, for review). All of the lipoprotein classes contain phospholipids, es-terified and unesterified cholesterol, and triglycerides to varying degrees. LDL are the most abundant lipoproteins in humans. They are... 

Procyclic forms do not synthesize cholesterol de novo but can incorporate this sterol if supplied exogenously de novo synthesis of ergosterol does occur. Bloodstream forms are able to acquire and incorporate the major mammalian bloodstream sterol into their membranes although they possess no ability to synthesize sterol de novo (63). The method of acquiring host cholesterol is of major significance. 

Trematodes do not synthesize cholesterol de novo, but acquire it from the host. Uptake occurs via the tegument, primarily at the dorsal surface of males (73), and the cholesterol is then redistributed throughout the body (74). Cholesterol, like glucose, is transferred between partners in copula (75). Other lipids are also transported across the tegument, and regionally specified areas of this surface may be involved (74). 

Why is synthesis of cholesterol de novo dependent on the activity of ATP-citrate lyase ... 

Phytosterols are of particular importance to insects, nematodes, and certain crustaceans, because they cannot synthesize cholesterol de novo. These organisms degrade dietary C28 and C29-phytosterols to C2 -sterols (usually cholesterol) or obtain C27-sterols directly from other organisms (Ikek-awa, 1983). These steroidal products are then used in the synthesis of biologically active sterols that the organisms require. There is evidence that dealkylation of phytosterols proceeds as indicated in (Fig. 23.14) (Harrison, 1985 Ikek-awa, 1983). 

The synthesis of cholesterol de novo from acetate is one of two sources of new cholesterol in both man and animals. It appears that every mammalian tissue is capable of at least some degree of de novo cholesterol synthesis, although there is great variation in synthetic activity among... 

Brouwers et al. (1996) have discussed some interesting functions of lipids in parasitic worms. For instance, the surface of adults of the human blood fluke Schistosoma mansoni consists of two closely apposed lipid bilayers (double bilayers), an apparent morphological and functional adaptation to parasitism. This membrane complex provides an effective tool for defeating the host s immune system in various ways. Brouwers et al. (1996) also presented a schematic overview of lipid metabolism in adult parasitic worms of interest because these parasites cannot synthesize fatty acids or cholesterol de novo and must obtain these lipids from the host. 

Figure 23.2 presents some of these atypical sterols isolated from diflferent opisthobranchs, prosobranchs, and pulmonates. However, tracer-incorporation studies have demonstrated that some mollusks synthesize cholesterol de novo from acetate or mevalonate and others are able to dealkylate C29 sterols to cholesterol (Teshima, 1991). 

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

There is a single report of the dealkylation of a sterol side-chain in the whelk Buccinum undatum [52]. This organism also transformed 3H-lanosterol (33) to cholesterol (1), thus indicating its capability for de novo sterol biosynthesis. 

Jim, S., Ambrose, S. H. and Evershed, R. P. (2003b) Natural abundance stable carbon isotope evidence for the routing and de novo synthesis of bone FA and cholesterol. Lipids 38, 179 186. 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

Lp(a) binds to the LDL receptor on cultured fibroblasts, although with a lower affinity than LDL itself. Once bound, Lp(a) inhibits 3HMG-CoA reductase, indicating that it is taken up by the cells and by releasing its cholesterol moiety, regulates the de novo synthesis of cholesterol (FI 2). High plasma concentrations of Lp(a) can, by this mechanism, influence cholesterol metabolism. As the LDL/Lp(a) ratio in plasma is about 50-100/1, this influence is marginal. 

Cholesterol is required for membrane synthesis, steroid synthesis, and in the liver, bile acid synthesis. Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesized de novo. Most de novo synthesis occurs in the liver, vfhere cholesterol is synthesized from acetyl CoA in the cytoplasm. The citrate shutde carries mitochondrial acetyl CoA into the cytoplasm, and NADPH is provided by the HMP shunt and malic enzyme. Important points are noted in Figure 1-15-9,... 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

Figure 19.8 A brief summary of the pathways for formation and secretion of oestradiol and progesterone within the cells of the follicle. Cholesterol is taken up by thecal cells in a complex with low density lipoprotein. In the thecal cells, cholesterol is converted to testosterone which is released to be taken up by granulosa cells where it is converted into oestradiol. For synthesis of progesterone in the granulosa cells, cholesterol is synthesised de novo within the cells from acetyl-CoA. In the follicle the enzyme aromatase, which produces the aromab c ring in the female sex hormones, is restricted to the granulosa cells. The reacrions that are stimulated by LH and FSH increase synthesis and, therefore, secretion of testosterone and increased synthesis of oestrogens and progesterone.

Cholesterol The pathway for synthesis of cholesterol is described in Appendix 11.9. Cholesterol is important in the structure of membranes since it can occupy the space that is available between the polyunsaturated fatty acids in the phospholipid (Chapter 4). In this position, cholesterol restricts movement of the fatty acids that are components of the phosphoglycerides and hence reduces membrane fluidity. Cholesterol can be synthesised de novo in proliferating cells but it can also be derived from uptake of LDL by the cells, which will depend on the presence of receptors for the relevant apoUpoproteins on the membranes of these cells (Appendix 11.3). 

Orotic acid in the diet (usually at a concentration of 1 per cent) can induce a deficiency of adenine and pyridine nucleotides in rat liver (but not in mouse or chick liver). The consequence is to inhibit secretion of lipoprotein into the blood, followed by the depression of plasma lipids, then in the accumulation of triglycerides and cholesterol in the liver (fatty liver) [141 — 161], This effect is not prevented by folic acid, vitamin B12, choline, methionine or inositol [141, 144], but can be prevented or rapidly reversed by the addition of a small amount of adenine to the diets [146, 147, 149, 152, 162]. The action of orotic acid can also be inhibited by calcium lactate in combination with lactose [163]. It was originally believed that the adenine deficiency produced by orotic acid was caused by an inhibition of the reaction of PRPP with glutamine in the de novo purine synthesis, since large amounts of PRPP are utilized for the conversion of orotic acid to uridine-5 -phosphate. However, incorporation studies of glycine-1- C in livers of orotic acid-fed rats revealed that the inhibition is caused rather by a depletion of the PRPP available for reaction with glutamine than by an effect on the condensation itself [160]. 

Insect steroid metabolism has two biochemically distinctive components dealkylation of phytosterols to cholesterol and polyhydroxylation of cholesterol to ecdysone. We will focus on the first of these. Lacking the ability to synthesize sterols de novo, insects instead have evolved a dealkylation pathway to convert plant sterols to cholesterol(7-10). The dealkylation pathways are apparently absent in most other higher and lower organisms, which can convert mevalonate to squalene and thence into sterols( ). Specific insecticides are possible based on these biochemical differences. 

The liver meets the larger part (60%) of its requirement for cholesterol by de novo synthesis from acetylcoen-zyme-A. Synthesis rate is regulated at the step leading from hydroxymethyl-glutaryl CoA (HMG CoA) to mevalonic acid (p. 157A), with HMG CoA reductase as the rate-limiting enzyme. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

Mammalian cells acquire cholesterol either by de novo synthesis from acetyl-coen-zyme A (CoA) or via the low-density lipoprotein (LDL)-receptor-mediated uptake of LDL particles that contain cholesterol esterified with long-chain fatty acids. These LDL cholesterol esters are subsequently hydrolyzed in lysosomes, after which free cholesterol molecules become available for synthesis of membranes, steroid hormones, bile acids, or oxysterols [1]. 

De novo synthesis of cholesterol is catalyzed by the isoprenoid biosynthesis pathway. This pathway produces a variety of sterol and nonsterol isoprenoids with... 

Regulation of Cholesterol Biosynthesis Cholesterol in humans can be obtained from the diet or synthesized de novo. An adult human on a low-cholesterol diet typically synthesizes 600 mg of cholesterol per day in the liver. If the amount of cholesterol in the diet is large, de novo synthesis of cholesterol is drastically reduced. How is this regulation brought about ... 

Effect of endocytosed cholesterol on cellular cholesterol homeostasis The chylomicron remnant-, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several ways (see Figure 18.20). First, HMG CoA reductase is inhibited by ttfi cholesterol, as a result of which, de novo cholesterol synthesis decreases. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene, thus limiting further entry of LDL cholestrol into cells. [Note ... 

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