Cholesterol metabolism/transport

Lipoprotein metabolism is the process by which hydrophobic lipids, namely triglycerides and cholesterol, are transported within the interstitial fluid and plasma. It includes the transport of energy in the form of triglycerides from intestine and liver to muscles and adipose, as well as the transport of cholesterol both from intestine and liver to peripheral tissues, as well as from peripheral tissues back to the liver. 

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

A high plasma concentration of LDL (usually measured as LDL-cholesterol) is a risk factor for the development of atheroma whereas a high concentration of HDL is an anti-risk factor for cardiovascular disease (CVD). Fundamental discoveries relating to cholesterol metabolism and the importance of the LDL receptor made by Nobel laureates Joseph Goldstein and Michael Brown led to an understanding of the role of LDL in atherosclerosis. The impact of HDL in reducing CVD risk is often explained by the removal of excess cholesterol from tissues and its return to the liver, a process known as reverse cholesterol transport. However, evidence from research by Gillian Cockerill and others shows that HDL has a fundamental anti-inflammatory role to play in cardioprotection. 

The primary developmental mechanism of the atherosclerotic process is not completely understood. It seems likely that the development of atherosclerosis is preceded by metabolic abnormalities of the synthesis, transport, and utilization of lipids. Lipids such as triglycerides and cholesterol esters are circulated in the blood in the form of particles (lipoproteins) wrapped in hydrophilic membranes that are synthesized from phospholipids and free cholesterol. Cholesterol is transported by particles of various sizes synthesized from triglycerides, cholesterol esters, and phospholipids, each of which plays a very specific role. 

All of these biological roles of the steroids figure prominently in human well-being. Defects in cholesterol metabolism are major causes of cardiovascular disease. It is no wonder that steroids are a central concern in medical biochemistry. In this chapter we discuss the metabolism of these complex lipids and the plasma lipoproteins in which they and other complex lipids are transported to various tissues. 

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). 

Fig. 1. A model for the pleiotropic effects of LH on functions of Leydig cells. LH interacts with its specific receptor in the plasma membrane of the Leydig cell which results in the activation of several transducing systems and the formation of several second messengers (cyclic AMP, Ca2+, diacylglycerol and arachidonic acid metabolites). Protein kinases (A, C and calmodulin dependent) are activated resulting in the phosphorylation of specific proteins and the synthesis of specific proteins. The (phospho)proteins are involved in the transport of cholesterol to, and the control of, cholesterol metabolism in the inner mitochondrial membrane. Arachidonic acid metabolites (prostaglandins, leukotrienes) may also control steroidogenesis. LH can also regulate the secretion of proteins. The trophic effects of LH are manifested in the growth and differentiation of the Leydig cells.

Neurons rely upon a ready supply of cholesterol for maintaining a broad array of physiological functions such as membrane synthesis, myeUn maintenance, electrical signal transduction, synaptic transmission, and plasticity. Cholesterol metabolism in the CNS is unique compared with the rest of the body. Because of the existence of the blood-brain barrier (BBB), almost all the sterol required for new membranes comes from de novo synthesis within the CNS [33]. In addition, the brain has evolved highly efficient mechanisms to maximize the utihzation of cholesterol. UnUke other membrane lipid components, cholesterol cannot be synthesized at neuronal terminals. Therefore, synaptic function depends largely on cholesterol supplied from either axonal transport from the cell body and or uptake of Upidated ApoE produced by astroglia via neuronal lipoprotein receptors. 

The bile acids are 24-carbon steroid derivatives. The two primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the hepatocytes from cholesterol by hy-droxylation, reduction, and side chain oxidation. They are conjugated by amide linkage to glycine or taurine before they are secreted into the bile (see cholesterol metabolism. Chapter 19). The mechanism of secretion of bile acids across the canalicular membrane is poorly understood. Bile acids are present as anions at the pH of the bile, and above a certain concentration (critical micellar concentration) they form polyanionic molecular aggregates, or micelles (Chapter 11). The critical micellar concentration for each bile acid and the size of the aggregates are affected by the concentration of Na+ and other electrolytes and of cholesterol and lecithin. Thus, bile consists of mixed micelles of conjugated bile acids, cholesterol, and lecithin. While the excretion of osmotically active bile acids is a primary determinant of water and solute transport across the canalicular membrane, in the canaliculi they contribute relatively little to osmotic activity because their anions aggregate to form micelles. 

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... 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

The trafficking of lipoprotein-derived cholesterol from lysosomes has been a major area of focus in the field of intracellular cholesterol metabolism, and many of the cellular and molecular events are not known (Chapter 17). By analyzing cells with mutations in cholesterol transport, investigators have identified roles for two proteins, called NPCl and NPC2 (HEl), in lysosomal and/or endosomal cholesterol transport (E.J. Blanchette-Mackie, 2000 P. Lobel, 2000). In addition, the lipid lysobisphosphatidic acid and certain GTPases called Rab proteins may also play roles in these processes (J. Gruenberg, 1999 E. Ikonen, 2006). The mechanisms by which these molecules are involved in cholesterol transport, however, are poorly understood [14]. 

Cholesterol ester transport protein depletes HDL of cholesterol while concomitantly increasing the amount of cholesterol in the outward-going VLDL and LDL particles. At first glance, it may seem disadvantageous for cholesterol to remain in the atherogenic LDL and VLDL fractions of the lipoproteins. However, the mechanism scavenges cholesterol from the periphery, thus relieving cells of the metabolically expensive process of de novo synthesis. 

Martins IJ, Berger T, Sharman MJ, VerdUe G, FuUer SJ, Martins RN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer s disease. J Neurochem 111 1275-1308... 

The cholesterol resorption inhibitor ezetimibe, introduced to the market in 2003 as Zetia by the Merck company, works as well as a sequestrant. The compound localises at the brush border of the small intestine and selectively blocks the transport of cholesterol into the circulation and its hver storage. The reduction of the exogenous cholesterol metabolism leads eventually to a drop in LDL cholesterol and a rise in HDL levels. [372]... 

Oxysterols are oxidized forms of cholesterol they are formed enzymatically in the first steps of cholesterol metabolism, and they may also be formed as a result of autoxidation of cholesterol [50]. The high abundance of cholesterol in biological systems means that oxysterols can easily be formed nonenzymatically during sample handling and workup unless care is taken. Oxysterols are biologically active molecules they have been shown in vitro to activate nuclear receptors, for example, liver X receptors (LXRs) [51], to interact with INSIG protein and thereby to repress cholesterol synthesis [52], and, like bile acids, to interact with G-protein coupled receptors. Oxysterols also represent transport forms of cholesterol [53] (Table 2.3). 

The esterification of cholesterol in animals has attracted considerable research because of the possible involvement of cholesterol and its ester in various disease states (cf. Glomset and Norum, 1973, and Sections 12.1, 12.3 and 12.6). Cholesterol esters are formed by the action of lecithin cholesterol acyltransferase (LCAT, EC 2.3.1.43) which is particularly active in plasma (cf. Sabine, 1977, for a review of cholesterol metabolism). The reaction involves transfer of a fatty acid from position 2 of lecithin (phosphatidylcholine) to the 3-hydroxyl group of cholesterol with the formation of monoacyl-phosphatidylcholine. Although LCAT esterifies plasma cholesterol solely at the interface of high-density lipoprotein and very-low-density lipoprotein, the cholesterol esters are transferred to other lipoproteins by a particular transport protein (CETP cholesteryl ester transfer protein). Cholesteryl esters, in contrast to free cholesterol, are taken up by cells mostly via specific receptor pathways (Brown et aL, 1981), are hydrolysed by lysosomal enzymes and eventually re-esterified and stored within cells. LCAT may also participate in the movement of cholesterol out of cells by esterifying excess cholesterol in the intravascular circulation (cf. Marcel, 1982). 

The cholesterol-rich LDL particles are notorious as the bad guys of lipoprotein metabolism. On the other hand, HDL particles enjoy the reputation as the good guys . This is because the function of HDL is to remove surplus cholesterol and transport it to the liver for disposal as bile salts. 

Fatty acids in phospholipids are important for maintaining the function and integrity of cellular and subcellular membranes. These acids also play a role in the regulation of cholesterol metabolism—especially its transport, breakdown, and ultimate excretion. In addition, fatty acids have been shown to be the precursors for a group of hormonelike compounds called prostaglandins, which are important in the regulation of widely diverse physiological processes. 

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