Function of cholesterol

Functions of Cholesterol is a steroid. It is an important constituent of cell membranes,... 

Cholesterol is a basic constituent of cell membranes and is known to affect their properties [10]. Thus experiments with liposomes incorporating varying amounts of cholesterol may simulate the function of cholesterol in cell mem-... 

The stratum corneum intercellular lipids exist as a continuous lipid phase occupying about 20% of the stratum corneum volume and arranged in multiple lamellar structures. They are composed of cholesterol (27 /o) and ceramides (41 /o), together with free fatty acids (9 /o), cholesteryl esters (10 /o) and cholesteryl sulfate (2 /o) (Table 1). Phospholipids, which dominate in the basal layer, are converted to glucosylceramides and subsequently to ceramides and free fatty acids, and are virtually absent in the outer layers of the stratum corneum. Eight classes of ceramides have been isolated and identified in human stratum corneum but the functions of the individual ceramide types are not fully understood. Similarly, the exact function of cholesterol esters within the stratum corneum lamellae is also elusive but it is theoretically possible that cholesterol esters may span adjacent bilayers and serve as additional stabilizing moieties. 

The most vital function of cholesterol in animals is as a structural element in cell membranes. About 90% of the imesterified cholesterol in the cell is located in the plasma membrane. OrUy a small proportion occurs in internal membranes and in the lipid droplets of the cytoplasm. For example, the cholesterohphospholipid ratio in the plasma membrane (PM) is about l.Orl.O but that in the ER is about 0.1 1.0 (Straka et al, 1990). The cholesterohphospholipid ratio controls the viscosity of the membrane. Higher ratios result in a more viscous, less fluid membrane. The ER consists of a network of branching tubules. A fluid-like behavior has been observed in the ER of living cells observed imder a microscope. Individual branches may move along the tubules and migrate over the surfaces of neighboring branches (Lee and Chen, 1988). 

Gel to liquid-crystal melting transition for DPPC liposomes as a function of cholesterol content. Results are shown for aqueous liposomes (stars), liposomes freeze-dried without trehalose (triangles), and liposomes freeze-dried in the presence of trehalose (circles). 

Fig. 16. Isothermal compressibility data of DPPC-cholesterol mixtures as a function of cholesterol concentration and pressure at T= 50 °C [98].

It is not possible to write a comprehensive review of cholesterol biosynthesis in the space allotted nor is it our desire to do so. Consequently, we have been selective as to what has been included and the list of references is far from exhaustive. We hope that no one will be offended by our choices. In addition, where appropriate, the stress has been on enzymes from Uver. There are several recent and comprehensive reviews on cholesterol biosynthesis. Two books, one by Nes and McKean [1] and another by Gibbons, Mitropoulos and Myant [2] provide excellent and current reviews on the biosynthesis and function of cholesterol. In addition, about half of the chapters in a book edited by Porter and Spurgeon [3] deal with selected aspects of the biochemistry of sterologenesis and, taken as an aggregate, provide a comprehensive review of the subject. Also Schroepfer has published recently two reviews on cholesterol biosynthesis in Annual Reviews of Biochemistry [4,5]. 

A similar kinetic approach has been used to measure the specific activity of rat liver cytosol or of protein fractions obtained during the purification of SCP2 [21]. As with purified SCP2, the velocity of cholesterol formed is a hyperbolic function of the amount of cytosol protein present. As before, a straight line is obtained when the velocity of cholesterol formation is plotted as a function of cholesterol formed per mg of rat liver cytosol [21]. The purification factor for SCP2 can be calculated from X intercept for rat liver cytosol/2f intercept for purified SCP2. Using this approach [21], a purification factor of 1300-1400-fold was obtained. 

Fig. 2. Activity of homogeneous SCP2 as measured in the activation of the conversion of 7-dehydro-cholesterol to cholesterol by rat liver microsomes. Incubations were conducted as described [21] except that the incubation volume was 0.6 ml. (A) Cholesterol formed is plotted as a function of SCPj protein. (B) Cholesterol formed is plotted as a function of cholesterol formed per mg of SCPj.

The organisation and function of cholesterol in biological membranes and the possible interactions with other Upids and proteins need to be clarified in order to achieve an understanding of many ceUular functions at the molecular level. Various disease conditions have been linked with abnormal cholesterol concentrations in cell membranes. Recently the evolutionary development of cholesterol and its role in membrane speciaUsation have become of some interest. 

In addition to Its structural role In membranes, discussed In Chapter 5, cholesterol Is the precursor for several Important bloactive molecules. They Include bile acids (see Figure 18-6), which are made In the liver and help emulsify dietary fats for digestion and absorption In the Intestines, steroid hormones produced by endocrine cells (e.g., adrenal gland, ovary, testes), and vitamin D produced In the skin and kidneys. Arthropods need cholesterol or other sterols to produce membranes and ecdysterold hormones, which control development however, they cannot make the precursor sterols themselves and must obtain these compounds In their diet. Another critical function of cholesterol Is Its covalent addition to Hedgehog protein, a key signaling molecule In embryonic development (Chapter 15). 

It is evident that one function of cholesterol is structural because it is the most common single lipid molecule in the plasma membrane of mammals. Yet cholesterol may also have other functions. What aspects of cholesterol and its metabolism lead to the conclusion that cholesterol is a multifunctional membrane lipid ... 

In 1888 the Austrian botanist and chemist Friedrich Reinitzer, interested in the chemical function of cholesterol in plants, noticed that the cholesterol derivative cholesteryl benzoate had two distinct melting points. At 145.5°C (293.9°F) the solid compound melted to form a turbid fluid, and this fluid stayed turbid until 178.5°C (353.3°F), at which temperature the turbidity disappeared and the liquid became clear. On cooling the liquid, he found that this sequence was reversed. He concluded that he had discovered a new state of matter occupying a niche between the crystalline solid and liquid states the liquid crystalline state. More than a century after Reinitzer s discovery, liquid crystals are an important class of advanced materials, being used for applications ranging from clock and calculator displays to temperature sensors. 

Fig. 34.17. Function of cholesterol ester transfer protein (CETP). CETP transfers cholesterol esters (CE) from HDL to VLDL in exchange for triacylglycerol (TG).

Phenylalanine and related metabolites inhibit activity of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase (Fig. 9.2). This aizyme is critical for proper synthesis of cholesterol in phenylalanine-sensitive oligodendrocytes located in the frontal brain, especially in the prefrontal cortex. Locally synthesized cholesterol makes up approximately 30 % of all myelin lipids of the brain tissue. The function of cholesterol is not only structural but is also required for proper neuronal signal transmission [50]. Inhibition of HMG-CoA reductase by phaiylalanine is partially reversible in some individuals. This explains the improvement in myelination observed in MRl scans of poorly controlled patients who have returned to diet and have lowered their blood phenylalanine concentrations. The reduction in phenylalanine allows for proper myelin production in the phenylalanine-sensitive oligodendrocyte population [50,57,58] (Fig. 9.3). 

Tschesche R, Brennecke HR (1980) Side chain functionalization of cholesterol in the biosynthesis of solasodine in Solarium laciniatum. Phytochemistry 19 1449—1451 Tschesche R, Gutwinski H (1975) Steroidsaponine mit mehr als einer Zuckerkette. X. Capsicosid, ein bisdesmosidisches 22-Hydroxyfurostanolglycosid aus den Samen von Capsicum annuum L. Ber 108 265-272... 

In an attempt to compare the physical state of the bilayers with the extent of hydrogen bonding to the keto group of 9HP, as a function of cholesterol concentration, we studied the temperature dependence of the CH2 symmetric stretching vibrational modes, (CH2). (24)... 

Figure 20. DSC curves of DSPC/cliolesterol mixtures as a function of cholesterol content (adapted from reference [67]),...

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