Intestinal cholesterol

Enzymatic Conversion of Cholesterol. A decrease of cholesterol in meat products in the future may be possible through the conversion of cholesterol [57-88-5] to coprosterol [560-68-9] which is not absorbed readily in the intestine. Cholesterol reductase can be isolated from alfalfa leaves and cucumber leaves (53). Treatment of meat animals might involve an injection of this ensyme immediately prior to slaughter, allowing for the conversion of a portion of the membrane-bound cholesterol into coprostanol. 

DAWSON P A, rudel l l (1999) Intestinal cholesterol absorption. Curr Opin Lipidol. 10 315-20. 

Atmann, S.W. et al., Niemann-Rick Cl Like 1 protein is critical for intestinal cholesterol absorption, Science, 303, 1201, 2004. 

Arjmandi, B. H., Craig, J., Nathani, S., and Reeves, R. D. (1992). Soluble dietary fiber and cholesterol influence in vivo hepatic and intestinal cholesterol biosynthesis in rats. /. Nutr. 122,1559-1565. 

Mechanism of Action An antihyperlipidemic that inhibits cholesterol absorption in the small intestine, leadingtoadecreasein the delivery of intestinal cholesterol to the liver. Therapeutic Effect Reduces total serum cholesterol, LDL cholesterol, and triglyceride levels and increases HDL cholesterol concentration. 

The two significant sources of cholesterol in body are endogenously synthesized cholesterol and exogenous or dietary cholesterol. Efforts to inhibit the absorption of dietary cholesterol have primarily focused on the inhibition of ACAT, a major enzyme associated with cholesterol esterification. Inhibition of this enzyme blocks the absorption of intestinal cholesterol and may also inhibit cholesteryl ester deposition in the vascular wall in the form of fatty streaks associated with atherosclerotic plaque. 

Eckhardt, E. R. M., Wang, D. Q. H., Donovan, J.M., and Carey, M.C. 2002. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers. Gastroenterology 122, 948-956. 

Heinemann, T., Pietruck, B., Kullak-Ublick, G., and von Bergmann, K. 1988. Comparison of sitosterol and sitostanol on inhibition of intestinal cholesterol absorption. Agents Actions... 

The search for intestinal cholesterol transporters extended for many years, beginning with a debate about whether or not it was even a protein-facilitated process (4, 5). The pancreatic enzyme carboxyl ester lipase (CEL, also called cholesterol esterase) was believed to be important to this process (6,7) and several companies devoted considerable resources to the development and testing of compounds to inhibit CEL, with mixed results (8-10). These efforts were abandoned in the mid-1990s, however, after studies with gene-knockout mice demonstrated that the enzyme was important only for absorption of cholesteryl ester (11, 12), which is a minor component of dietary cholesterol and is present at very low levels in bile. Interestingly, CEL is also found in liver where it has been shown to affect HDL metabolism (13). Thus, it may ultimately play an important role in cholesterol metabolism and may yet prove to be a useful drug target for CVD treatment (Camarota and Howies, unpublished). 

Levy, E., Spahis, S., Sinnett, D., Peretti, N., Maupas-Schwalm, F., et al. (2007) Intestinal cholesterol transport proteins an update and beyond. Curr. Opin. Lipidol. 18, 310-318. 

An opposite effect is at the basis of the up-regulation of LDL receptors in response to treatments with bile acid sequestrants, intestinal cholesterol absorption inhibitors, and HMG-CoA reductase inhibitors. The first class of drugs inhibits the intestinal reabsorption of bile acids, thus promoting increased conversion of cholesterol to bile acids in the liver. The increased demand for cholesterol results in activation of the SREBP system and upregulation of LDL receptor synthesis (as well as cholesterol synthesis via upregulation of HMG-CoA reductase). Similarly, inhibition of intestinal cholesterol absorption with ezetimibe results in a reduction in the hepatic cholesterol pool... 

M. Werder, H. Hauser, S. Abele, D. Seebach, p-Peptides as Inhibitors of Small-Intestinal Cholesterol and Fat Absorption , Helv. Chim. Acta 1999, 82, 1774 - 1783. 

The distillate obtained from sunflower oil may be sold to pharmaceutical companies for tocopherol and sterol isolation. Tocopherols may be used as natural antioxidants or may be converted to vitamin E by methylating the heterocyclic ring. The interest in phytosterols is caused by the high potential of some of them to inhibit intestinal cholesterol absorption. 

Ezetimibe is used for secondary prevention against established atherosclerotic CVD to achieve an optimal atherogenic cholesterol level in patients with intolerance to high-doses of statins. It can further be used in combination with statins to achieve lower LDL-C levels in very-high-risk patients [59]. Ezetimibe inhibits the Niemann-Pick Cl-Like 1 (NPClLl)-dependent intestinal cholesterol absorption in the apical brush border membrane of jejuna enterocytes [14], and thus it only moderately lowers LDL-C (12-25 %) [60]. Meanwhile, common adverse effects associated with ezetimibe therapy include gastrointestinal disturbances, while infrequent adverse effects such as rash, angioedema, anaphylaxis, hepatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis may occur [46]. 

Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP (2004) Niemann-Pick Cl Like 1 protein is critical for intestinal cholesterol absorption. Science 303 1201-1204... 

Probucol (Figure 20-12) significantly reduces plasma cholesterol levels but has no effect on triacylglycerols. It may act via blockage of intestinal cholesterol transport. HDL cholesterol levels are reduced by this drug. No consistent side effects have been reported. 

Recent investigations into the mechanism of action of these bile acids indicate that ursodeoxycholic acid has certain advantages over chenodeoxycholic acid in the context of the overall homeostasis of cholesterol metabolism (F6). In contrast to chenodeoxycholic acid, ursodeoxycholic acid does not suppress bile acid synthesis (H7), possibly because the a-orientation of the 7-hydroxyl group of chenodeoxycholic acid is required to inhibit cholesterol 7a-hydroxylase activity. Thus, cholesterol breakdown into bile acids is not reduced by ursodeoxycholic acid. Other favorable factors are that ursodeoxycholic acid has a reduced capacity to solubilize cholesterol into micellar solution compared to chenodeoxycholic acid and intestinal cholesterol absorption is decreased by this bile acid (F6, H7). However, in gallbladder bile the relative limitation of ursodeoxycholic acid for micellar solubilization of cholesterol is compensated for by an ability to transport... 

Similar problems have compUcated the quantitation of HMG-CoA reductase activity as a measure of the rate of cholesterol synthesis. For example, it has not been established as firmly for the intestine as for the hver that this enzyme is rate limiting to the overall synthesis of the cholesterol molecule [23]. Furthermore, HMG-CoA reductase in both the intestine and liver is subject to a phosphorylation-dephosphorylation reaction that modifies enzyme activity and is involved in the activation of an inactive (phosphorylated) to an active (dephos-phorylated) form during homogenization of the mucosa [24,25]. Finally, HMG-CoA reductase is incompletely recovered from the mucosa during preparation of micro-somes [26,27] and is very sensitive to inactivation by proteases present in the intestine [28]. These various technical problems have led to considerable confusion with respect to various aspects of intestinal cholesterol synthesis and have made it difficult to interpret quantitatively some of the results presented below. 

In contrast to the extensive literature on the regulation of intestinal cholesterol synthesis, only a few studies are available on regulation of lipoprotein uptake in this organ. Notably, recent studies have compared the effect of various interventions such as the feeding of cholesterol, cholestyramine, surfomer, and com oil on both rates of cholesterol synthesis and LDL transport in the rat intestine in vivo, as shown in Fig. 9. While these various manipulations all alter rates of cholesterol synthesis, there is no consistent effect upon LDL uptake at any location in the mucosa, with the possible exception of a slight increase in the jejunum after feeding... 

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