Mechanism of cholesterol

Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M. and Russell, D. W. Knockout of the cholesterol 24-hydroxy-lase gene in mice reveals a brain-specific mechanism of cholesterol turnover. /. Biol. Chem. 278 22980-22988, 2003. 

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

This article focuses on specific dietary components—whether naturally occurring or added as food ingredients—known to interfere with the mechanisms of cholesterol absorption. An overview of cholesterol absorption is provided and emphasizes the critical role of bile acids and micelle formation in solubilizing cholesterol for transport to the brush border membrane of enterocytes. Where applicable, information is also included about commercial food ingredients that are specifically used as cholesterollowering agents. 

Hui, D.Y. and Howies, P.N. 2005. Molecular mechanisms of cholesterol absorption and transport in the intestine. Semin. Cell Dev. Biol. 16, 183-192. 

Trautwein, E.A., Rieckhoff, D., and Erbersdobler, H.F. 1998. Dietary inulin lowers plasma cholesterol and triacylglycerol and alters biliary bile acid profile in hamsters. J. Nutr. 128, 1937-1943. Trautwein, E.A., Duchateau, G. S. M. J.E., Lin, Y., Molhuizen, S.M., Mel nikov, H. O. F., and Ntanios, F.Y. 2003. Proposed mechanisms of cholesterol lowering action of plant sterols. Eur. 

In this light, cholesterol absorption has received intense focus for several decades. Although the various statins lower LDL by decreasing endogenous cholesterol synthesis, another approach to prevent excess cholesterol accumulation is to reduce absorption of dietary cholesterol. Doing so also prevents reabsorption of biliary cholesterol, which can have a major impact on overall cholesterol metabolism since recirculation of biliary cholesterol represents a large portion of the cholesterol that transits through the intestine. For recent reviews on mechanisms of cholesterol and lipid absorption, see ref. (1-3). 

Bahr, J. M., Frayha, G. J. Hajjar, J. J. (1979). Mechanism of cholesterol absorption by the hydatid cysts of Echinococus granulosus (Cestoda). Comparative Biochemistry and Physiology, 62A 485-9. 

Higuchi, W.I. Su, C.C. Park, J.Y. Gulari, E. Mechanism of cholesterol gallstone dissolution. Analysis of the kinetics of cholesterol monohydrate dissolution in taurocholate/ lecithin solutions by the mazer, benedek, and carey models. J. Phys. Chem. 1981, 85 (2), 127-129. 

However, foUowing enrichment of the cells with exogenous cholesterol or incubation with 0.1 mM chlorpromazine [156], the whole of the cholesterol pool becomes available to the cholesterol oxidase. This means that the time-course of cholesterol oxidation can be determined and hence the rate of flip-flop. Based on such studies, a half-time of less than 3 sec at 37°C has been found for transposition of cholesterol across the bilayers [157]. These studies have also been extended to probe features of lipid-cholesterol organisation in the human erythrocyte membrane [158]. Clearly, such studies are relevant to our understanding of the mechanisms of cholesterol loss from cells in vivo by the methods outhned earlier. 

Fig. 5. Modification of hedgehog with ester-linked cholesterol and an N-terminal amide-linked fatty acid (redrawn from Ref. [14]). (A) Overall processing steps leading to lipid-modified Hedgehog (Hh). (B) Mechanism of cholesterol addition. Residues indicated as B1 and B2 in panel B are catalytic bases presumably contained in the carboxy-terminal domain of the Hh precursor.

Important insights into the mechanism of cholesterol transport have come from LDL metabolism in cells from individuals with NPC disease [30]. In NPC fibroblasts, cholesterol transport from the lysosomal compartment to the plasma membrane is markedly retarded compared to that in normal fibroblasts (L. Liscum, 1999 E. Blanchette-Mackie, 2000). The transport defect results in the accumulation of cholesterol in lysosomes and endosomes. NPC cells also have impaired regulation of acyl-CoA cholesterol acyltransferase, 3-hydroxy-3-methylglutaryl-Co A reductase, and LDL receptor levels, in response to LDL (Chapter 14). In contrast, the transport of newly synthesized cholesterol from the ER to the plasma membrane of NPC fibroblasts is essentially identical to that found for normal cells. These findings localize one abnormality of NPC disease to cholesterol export from the lysosomes to other organelles. 

A.M. van Bennekum, D.V. Nguyen, G. Schulthess, H. Hauser, and M.C. Phillips, Mechanisms of cholesterol-lowering effects of dietary insoluble fibres Relationships with intestinal and hepatic cholesterol parameters, Br. J. Nutr, 94 (3), 331-337, 2005. 

After Schoenheimer s untimely death in 1941, his associates fell heir to a wealth of problems and ideas which had been conceived and begun under his leadership. Continuing on our own, we may have divided the program according to personal preferences or by tossing coins. How these fateful decisions were made I do not recall. At any rate, D. Rittenberg and I began to collaborate on the mechanism of cholesterol biosynthesis. 

This fundamental role of bile salts in the intestinal absorption of sterols is a reflection of the potential requirements for this cholesterol metabolites in various steps of intraluminal and epithelial cell mechanisms of cholesterol absorption (Figure 1), These include solubilization of cholesterol in the intestinal lumen by mixed micelles, containing biliary bile salts and phospholipids, and the products of triglyceride digestion modification of the intestinal surface barriers to cholesterol transfer, including the un-stirred water layer" and the mucin "coat" and the cellular esterification of cholesterol prior to incorporation of the resulting esters into the lipoprotein core lipids. 

The precise mechanism of cholesterol transport from the micelles into the... 

Di Scala C, Troadec JD, Lelievre C, Garmy N, Fantini J, Chahinian H. Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer beta-amyloid peptide. / Neurochem. 2013. 

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