Cholesterol metabolic fate

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A B-48, apolipoprotein B-48 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylgiycerol C, cholesterol and cholesteryl ester P, phospholipid HL, hepatic lipase LRP, LDL receptor-reiated protein.) Only the predominant lipids are shown.

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

Biosynthesis represents the major metabolic fate of cholesterol, accounting for more than half of the 800 mg/day of cholesterol that the average adult uses up in metabolic processes. By comparison, steroid hormone biosynthesis consumes only about 50 mg of cholesterol per day. Much more that 400 mg of bile salts is required and secreted into the intestine per day, and this is achieved by recycling them. Most of the bile salts secreted into the upper region of the small intestine are absorbed along with the dietary lipids that they emulsified at the lower end of the small intestine. They are... 

Radioactive carbon dioxide was detected in the breath of rats and men almost immediately after the administration, either orally or by injection, of (RS)-[5-14C]MVA,36 and up to 6.5% of the administered dose was exhaled within 100 minutes. Since the carbon dioxide was not derived from the unnatural S-enantiometer of MVA, or from degradation of cholesterol biosynthesized from the additive MVA, the observations support the hypothesis that there exists a metabolic shunt of intermediates of sterol biosynthesis which, although derived from MVA, do not lead to sterol formation. The significance of this shunt is that its occurrence could explain some of the human hypercholesterolaemias. The authors claim that MVA has no metabolic fate (hitherto known) except the biosynthesis of terpenoids is quite... 

Differences in nutritional effects between PLs and TAGs can be caused by several factors not related to their fatty acid composition, such as the presence of a phosphate group and a nitrogen base (mainly chohne) that may interact in several metabolic pathways (82). Moreover, several glycerophospholipid preparations studied can contain other components such as cholesterol, cerebrosides, sphingomyelins also depending on their source, method of isolation, and purification. These components may also affect the nutritional properties. In this chapter, the metabolic fate of constituent fatty acids of PLs and TAGs will be compared. 

Pyruvate has several metabolic fates. It can be reduced to lactate, converted to oxaloacetate in a reaction important in gluconeogenesis (Chapter 15) and in an anaplerotic reaction of the TC A cycle (see below), transminated to alanine (Chapter 17), or converted to acetyl-CoA and CO2. Acetyl-CoA is utilized in fatty acid synthesis, cholesterol (and steroid) synthesis, acetylcholine synthesis, and the TCA cycle (Figure 13-6). 

The possibUity of multiple pathways in bile acid biosynthesis in man has been discussed by Vlahcevic et al. [180-182]. A number of labelled 7 -hydroxylated intermediates in bile acid biosynthesis were administered to bile fistula patients as well as patients with an intact enterohepatic circulation. In accordance with previous work with bile fistula rats, the spedfic activity of the isolated chohc add was in general considerably lower than that of chenodeoxychohc acid. On the basis of this finding, it was suggested that a portion of chohc acid was synthesized via a route not involving initial 7a-hydroxylation of cholesterol. It must then be assumed that the administered intermediate mixes with the endogenous pool of the same steroid. However, due to compartmentation, the metabolic fate of a precursor reaching the hepatocyte might be different from that of the the same compound formed within the cell. Normally, the different precursors are present in the cells in trace amounts... 

HP-P-CyD, respectively. Since the nephrotoxicity of natural 3-CyD at higher doses was ascribed to the crystallization of less-soluble P-CyD or its cholesterol complex in renal tissues,the metabolic fates of G2-3-CyD and HP-p-CyD are suggestive of lower renal toxicity compared with the parent p-CyD. To assess tolerance via the parenteral administration route, various blood chemistry parameters in rats and rabbits after the multiple intravenous administrations of hydrophilic P-CyDs were compared with those of the parent p-CyD. Multiple injections of p-CyD or DM-P-CyD at a total dose of 900 mg kg in rats and 1200 mg kg in rabbits produced some kidney and liver failure, while those for HP-P-CyD, G2-p-CyP and p-CyD sulfate at the same doses failed to induce any kidney or liver failure. 

The metabolic fate and physiological effects of phytosterol oxides in humans are not known. However, the cytotoxicity of oxides 3-sitosterol/campesterol in a culture-derived macrophage cell line was shown (Adcox et al., 2001). The toxic effects of these oxides were similar to those of cholesterol oxides, although less severe. These results would suggest that foods high in phytosterols should be monitored for their potential contribution to dietary risk factors associated with the consumption of their oxidation products. 

Bile salt production and the esterification with a fatty acid are the only metabolic fates of cholesterol. It is not oxidized to carbon dioxide, so any excess is excreted in the bile. 

One of the metabolic fates of the cholesterol that arrives in the liver is conversion to bile salts (Sec. 12.3). 

Of the a-linolenic acid ingested some is incorporated into phosphohpids and cholesterol esters, while very Kttle is elongated and eventually converted into prostaglandins most a-linolenic acid probably is used as fuel. Of the EPA and DHA ingested most likely a greater percentage ends in eicosanoid synthesis. Therefore, different polyunsaturated fatty acids of the (o-3 series cannot be considered as similar with respect to their metabolic fate and their effects. In particular results from experiments... 

CI-976 was synthesized as a fatty acid anilide derivative designed to mimic fatty acyl-CoA, the fatty acid donor for ACAT enzymes, and it has been most extensively studied in this regard as a competitive ACAT inhibitor (Field et al., 1991 Roth et al., 1992). Various animal studies have shown that CI-976 lowers plasma low density Upoprotein (LDL)-cholester-ol and raises high density lipoprotein-cholesterol by inhibiting both hver and intestinal ACAT activities CI-976 also lowers liver cholesterol esters (CE) and decreases CE secretion (Carr et al., 1995 Krause et al., 1993). The metabolic fate of CI-976 has been studied in both whole animals and isolated hepatocytes, and it is oxidized to numerous metabolites, likely by cytochrome P450 pathways (Sinz et al., 1997). The biological activities of these metabolites are unknown. 

The metabolism of cholesterol in mammals is extremely complex. A summary sketch (fig. 20.24) helps to draw the major metabolic interrelationships together. Cholesterol is biosynthesized from acetate largely in the liver (fig. 20.24a) or taken in through the diet (fig. 20.24b). From the intestine, dietary cholesterol is secreted into the plasma mainly as a component of chylomicrons. The triacylglycerol components of chylomicrons are quickly degraded by lipoprotein lipase, and the remnant particles are removed by the liver. Apoproteins and lipid components of the chylomicrons and remnants appear to exchange with HDL. Cholesterol made in the liver (fig. 20.24a) has several alternative fates. It can be (1) secreted into plasma as a component of VLDL,... 

Acetyl CoA. The major sources of this activated two-carbon unit are the oxidative decarboxylation of pyruvate and the P-oxidation of fatty acids (see Figure 30.11). Acetyl CoA is also derived from ketogenic amino acids. The fate of acetyl CoA, in contrast with that of many molecules in metabolism, is quite restricted. The acetyl unit can be completely oxidized to CO2 by the citric acid cycle. Alternatively, 3-hydroxy-3-methylglutaryl CoA can be formed from three molecules of acetyl CoA. This six-carbon unit is a precursor of cholesterol and of ketone bodies, which are transport forms of acetyl units released from the liver for use by some peripheral tissues. A third major fate of acetyl CoA is its export to the cytosol in the form of citrate for the synthesis of fatty acids. 

Acyl-CoA cholesterol acyltransferase (ACAT) esterifies free cholesterol by linking it to a fatty acid. ACAT is an intracellular enzyme that prepares cholesterol for storage as in liver parenchymal cells. The roles of these enzymes in lipoprotein metabolism will become more apparent in the discussion of the origin and fate of each class of lipoprotein. 

Bile salts perform an important function and are recycled by the body. The body produces 400 mg of bile salts per day from cholesterol this represents the fate of half of the cholesterol nsed daily in metabolism (800 mg). However, 20 to 30 g of bile acids is maintained in the enterohepatic circnlation. Less than 0.5 g per day is lost to excretion. Bile salts are produced in the liver, stored in the gallbladder, and secreted through the bile duct into the dnodennm where they act on triacylglycerol molecules in the intestines. In the gnt, the glycine or tanrine moiety is removed from the bile salt. It is reabsorbed in the small intestine and retnmed to the liver for rense via the portal vein. Bile salts are absorbed by passive diffnsion along the entire small intestine, and a specialized Na+-bile salt cotransporter is present in the lower ilenm. 

I he metabolism of fatty acids and lipids revolves aroimd the fate of acetyl Co A. We saw in Chapter 22 that, under aerobic conditions, p)mivate is converted to acetyl CoA, which feeds into the citric acid cycle. Fatty acids are also degraded to acetyl CoA and oxidized by the citric acid cycle, as are certain amino acids. Moreover, acetyl CoA is itself the starting material for the bios)mthesis of fatty acids, cholesterol, and steroid hormones. Acetyl CoA is thus a key intermediary in lipid metabolism. 

CHAPTER 34 / CHOLESTEROL ABSORPTION, SYNTHESIS, METABOLISM, AND FATE... 

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