Cholesterol synthesis stages

These hypolipidemic agents are noncompetitive inhibitors of the enzyme that limit the rate of cholesterol synthesis in the liver at the levalonic acid stage. 

In the next stage of cholesterol synthesis, three phosphate groups are transferred from three ATP molecules to mevalonate (Fig. 21-35). The phosphate attached to the C-3 hydroxyl group of mevalonate in the intermediate 3-phospho-5-pyrophosphomevalonate is a good... 

GC data should be evaluated carefully. The main sterols of interest are cholesterol and lathosterol, the latter being a late-stage intermediate in cholesterol synthesis. Coprostanol is formed by the action of colonic bacteria on cholesterol and may vary considerably between mice. Peaks for coprostanol and other minor animal-derived sterols appear very close to, and may overlap with, that of cholesterol. Lathosterol is usually resolved between the cholesterol and the first phytosterol peak. Neutral sterol excretion should be reported as the sum of cholesterol, its precursors, and its derivatives. Evaluation excluding precursors is also appropriate. 

Cholesterol is formed in the liver (85%) and intestine (12%) - this constitutes 97% of the body s cholesterol synthesis of 3.2 mmol/day (= 1.25 g/day). Serum cholesterol is esterized to an extent of 70-80% with fatty acids (ca. 53% linolic acid, ca 23% oleic acid, ca 12% palmitic acid). The cholesterol pool (distributed in the liver, plasma and erythrocytes) is 5.16 mmol/day (= 2.0 g/day). Homocysteine stimulates the production of cholesterol in the liver cells as well as its subsequent secretion. Cholesterol may be removed from the pool by being channelled into the bile or, as VLDL and HDL particles, into the plasma. The key enzyme in the synthesis of cholesterol is hydroxy-methyl-glutaryl-CoA reductase (HGM-CoA reductase), which has a half-life of only 3 hours. Cholesterol is produced via the intermediate stages of mevalonate, squalene and lanosterol. Cholesterol esters are formed in the plasma by the linking of a lecithin fatty acid to free cholesterol (by means of LCAT) with the simultaneous release of lysolecithin. (s. figs. 3.8, 3.9) (s. tab. 3.8)... 

Probucol increases the fractional rate of LDL catabolism. This effect may be linked to the increased excretion of fecal bile acids. Probncol also inhibits the early stages of cholesterol synthesis and slightly inhibits absorption of dietary cholesterol. There is no increase in the cyclic precursors of cholesterol hence, probncol does not appear to affect later stages of cholesterol biosynthesis. 

Treatment of PET inhibited cholesterol synthesis in cultured Hep G2 cells (Table I). The potential of PET to inhibit cholesterol synthesis was demonstrated by the incorporation of [2- H]acetate into cholesterol. PET inhibited cholesterol biosynthesis in a dose-dependent manner (Table I). The conversion of R-[2- CJmevalonate to cholesterol was not affected. Double-labeling experiment showed that PET inhibited cholesterol biosynthesis (40 pg/mL of PET had 56% inhibition) at the pre-mevalonate stage without affecting the post-mevalonate steps. In the assay system, fetal calf serum was maintained in DMEM. The IC50... 

On the other hand, in the synthesis of cholesterol (30) by Woodward and CO workers [10] the less stable fran -configuration between rings C and D is attained through a homosteroid (29). i.e. a steroid analogue in which the C/D indane system is substituted by a decalin in which the rran -configuration is the thermodynamically favoured (Scheme 8.7). The conversion of the six-membered ring into one of five members is carried out at a later stage, under conditions that do not affect the preformed tran -junction. 

Ethanol-related high levels of NADH+H and acetyl-CoA in the liver lead to increased synthesis of neutral fats and cholesterol. However, since the export of these in the form of VLDLs (see p. 278) is reduced due to alcohol, storage of lipids occurs (fatty liver). This increase in the fat content of the liver (from less than 5% to more than 50% of the dry weight) is initially reversible. However, in chronic alcoholism the hepatocytes are increasingly replaced by connective tissue. When liver cirrhosis occurs, the damage to the liver finally reaches an irreversible stage, characterized by progressive loss of liver functions. 

Synthesis takes place in four stages, as shown in Figure 21-33 (D condensation of three acetate units to form a six-carbon intermediate, mevalonate (2) conversion of mevalonate to activated isoprene units (3) polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene and ( ) cyclization of squalene to form the four rings of the steroid nucleus, with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol. 

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

This substance has been shown by tracer studies to be an efficient precursor of terpenes and steroids. Mevalonic acid has six carbon atoms, whereas the isoprene unit has only five. Therefore, if mevalonic acid is the precursor of isoprene units, it must lose one carbon atom at some stage. Synthesis of mevalonic acid labeled at the carboxyl group with 14C, and use of this material as a starting material for production of cholesterol, gives unlabeled cholesterol. Therefore, the carboxyl carbon is the one that is lost ... 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

A [ 1,7]H shift occurs in the final stages of the human body s synthesis of vitamin D from cholesterol. Here is the last step of the biosynthesis. 

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