Cholesterol transfer

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],... 

After triglyceride is removed from the VLDL, the resulting partide is referred to as either a VLDL remnant or as an IDL. A portion of the IDLs are picked up by hepatocytes through their apoE receptor, but some of the IDLs remain in the blood, where they are further metabolized. These IDLs are transition particles between triglyceride and cholesterol transport. In the blood, they can acquire cholesterol transferred from HDL particles and thus become converted into LDLs, as shown in Figure 1-15-6. 

LDL particles, are prodnced. The removal from the HDL prodnces a form that is less effective in reverse cholesterol transfer. The latter is a benehcial process since it transfers cholesterol from cells in varions tissues to the liver (see below). 

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

Figure 2 PMFs and density profiles for cholesterol in a SSM and POPC bilayer, a, b Partial density profiles for the two bilayer systems. The cholesterol density was multiplied by a factor of 20 for visualization, c, d PMFs for cholesterol transfer from equilibrium of the respective bilayer to bulk water. The center of mass of the cholesterol molecule was restrained with respect to the center of the bilayer. Reprinted with permission from ref. 46. Copyright 2009 American Chemical Society.

Zhang, Z., Lu, L., Berkowitz, M.L. Energetics of cholesterol transfer between lipid bilayers. J. Phys. Chem. B 2008, 112, 3807-11. 

Studies on the perfused rabbit liver suggest that rabbit LTP-I is produced by the liver (A2). Although models of esterified cholesterol transfers between lipoproteins (mediated by LTP) have been described (B7, 13) there is little information on LTP-I metabolism derived from direct studies. 

Determination of the rates of esterified cholesterol transfer between plasma lipoproteins has allowed the construction of a model of cholesteryl ester transfer (B7). According to this model, the probability of LTP-I picking up or depositing a molecule of esterified cholesterol in HDL or VLDL or LDL is in the proportion of approximately 30 7 1. Although the probability of in-... 

The rate of cholesterol esterification in plasma is not correlated with HDL concentration (A12, R17, S45, S58, Wl, W2) but is correlated with the concentration of VLDL or triglyceride (A12, P8, R17, S58, T7, Wl, W2). Although HDL is the major substrate for LCAT, VLDL and indirectly LDL are the major recipients of the esterfied cholesterol, transferred (it is thought) by lipid transfer protein. Accumulation of esterified cholesterol in the recipient lipoproteins is associated with a decrease in LCAT activity (C7, Fll, F13) that can be relieved by the addition of recipient lipoproteins but not by addition of LCAT substrate (Fll). Hopkins and Barter (H32, H33) have explained these observations by showing that the depletion of HDL esterified cholesterol by transfer to VLDL enhances the capacity of HDL to act as a substrate for LCAT. 

B15. Barter, P. J., and Lally, J. I., The activity of an esterified cholesterol transferring factor in human and rat serum. Biochim. Biophys. Acta 531, 233-236 (1978). 

H33. Hopkins, G. J., and Barter, P. J., Role of esterified cholesterol transfers in the regulation of plasma cholesterol esterification. Atherosclerosis 49, 177-185 (1983). 

Phospholipids are also thought to be involved in cholesterol transference. Increases in both the degree of unsaturation of fatty acyl groups and length of fatty acyl chains of mitochondrial phospholipids are known to increase the rate of cholesterol transfer [25]. Further, the concentrations of some phospholipids in the inner mitochondrial membrane of rat adrenals were shown to increase after ACTH stimulation and to be related to cholesterol SCC activity [25],... 

The different compositions of the plasma lipoproteins give a clue to their function. Essentially, those lipoproteins rich in TAGs are synthesized by the liver (VLDL) and small intestine (chylomicrons) and deliver the neutral fat to extrahepatic tissues (particularly adipose tissue). The fat-depleted lipoproteins have a higher density, and are involved in essential cholesterol transfers. 

The influence of CHL and Q3P on film morphology in monolayer mixtures with DPPC has been studied. Monolayers of DPPC as well as it mixtures tvith cholesterol, transferred by HP method, showed a molecularly smooth structure of uniform thickness. The addition of Q3P or CHL to DPPC, as investigated by AFM phase measurements, showed that a marked phase separation occurs in DPPC/Q3P mixtures or DPPC/SM/CHL films at small concentration of the alcohols, proving raft domain formation in the case of DPPC/SM/CHL films. 

High-Density Lipoprotein Reverse Cholesterol Transfer Pathway... 

Stocco, D.M. Intramitochondrial cholesterol transfer. Biochim. Biophys. Acta 1486 184-197, 2000. 

Some studies have also suggested that CYP46A1 polymorphisms may be linked to AD [135-145]. As discussed previously, 24S-hydroxycholesterol is an important regulator of ApoE -mediated cholesterol transfer from astrocytes to glia and excess 24S-hydroxycholesterol may be neurotoxic and pro-inflammatory [100,111,146-148]. Reports regarding statin effects on 24S-hydroxycholesterol have been mixed. Some studies demonstrated decreases in 24S-hydroxycholesterol levels following statin treatment [90,149,... 

Fig. 5. Stoicliiometric relationship between cholesterol mass transfer and SCP2. In A and B, the effect of SCP2 on net cholesterol mass released from adrenal lipid droplets and binding of cholesterol to SCP2 in the droplet-free subnatant is shown. The small amount of cholesterol transfer which occurred in the absence of SCP2 has been subtracted. In C and D, the effect of SCP2 on the depletion of cholesterol from the lipid droplets and the accumulation of cholesterol mass in aminoglutethimide-treated mitochondria is shown. Experimental details are described in ref. 33.

CETP is a plasma protein of unknown origin that transfers CE from one lipoprotein or artificially prepared bilayer to another (Fig. 2A). In addition to CE, the protein may also transfer other lipids such as TG or PC. It has been referred to as lipid transfer complex (ETC) [68,69], esterified cholesterol transfer/exchange protein (ECTEP) [70], CE transfer protein (CETP) [71], and lipid transfer fraction (LTP-1) [72]. The original observations regarding plasma CE transfer activity were made nearly 20 years ago [73], but even today the literature is confusing and incomplete and no generally accepted recent review is available. 

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. 

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