Plasma membrane cholesterol transport

Annaba F, Sarwar Z, Kumar P, Saksena S, Turner JR, Dudeja PK, Gill RK, Alrefai WA (2007) Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol association with lipid rafts. Am J Physiol Gastrointest Liver Physiol 294 489-497... 

The interaction of anandamide with plasma membrane cholesterol may also be linked to the mechanism of anandamide transport through a biological membrane. This issue has been greatly debated. As a lipid, anandamide is probably able to diffuse passively through the... 

The lipid compositions of plasma membranes, endoplasmic reticulum and Golgi membranes are distinct 26 Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues 26 In adult brain most cholesterol synthesis occurs in astrocytes 26 The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling 27 The structure and roles of membrane microdomains (rafts) in cell membranes are under intensive study but many aspects are still unresolved 28... 

Although apoE HDL particles are formed by astrocytes in vitro, the brain contents of apoE knockout (-/-) were not found to differ in lipid content in comparison to those obtained from normal animals [14]. A probable explanation is that newly synthesized cholesterol can be transported from astrocyte ER to plasma membrane via an alternative route that employs caveolae to form apoAl-HDL [15]. 

Lipids are transported between membranes. As indicated above, lipids are often biosynthesized in one intracellular membrane and must be transported to other intracellular compartments for membrane biogenesis. Because lipids are insoluble in water, special mechanisms must exist for the inter- and intracellular transport of membrane lipids. Vesicular trafficking, cytoplasmic transfer-exchange proteins and direct transfer across membrane contacts can transport lipids from one membrane to another. The best understood of such mechanisms is vesicular transport, wherein the lipid molecules are sorted into membrane vesicles that bud out from the donor membrane and travel to and then fuse with the recipient membrane. The well characterized transport of plasma cholesterol into cells via receptor-mediated endocytosis is a useful model of this type of lipid transport. [9, 20]. A brain specific transporter for cholesterol has been identified (see Chapter 5). It is believed that transport of cholesterol from the endoplasmic reticulum to other membranes and of glycolipids from the Golgi bodies to the plasma membrane is mediated by similar mechanisms. The transport of phosphoglycerides is less clearly understood. Recent evidence suggests that net phospholipid movement between subcellular membranes may occur via specialized zones of apposition, as characterized for transfer of PtdSer between mitochondria and the endoplasmic reticulum [21]. 

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],... 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

As the quantitatively predominant HDL component, apoA-I is crucial for HDL formation. It is also needed to activate LCAT and to mediate the interaction between HDL and cell surface receptors, such as scavenger receptor B1 or plasma membrane transporters such as ABCA1 [42]. Numerous non-sense and missense mutations in the apoA-I gene have been found to interfere with the formation of HDL, and to cause gene-dose-dependent decreases in HDL cholesterol, with a virtual absence of HDL in homozygotes and half-normal levels of HDL cholesterol in heterozygotes [22, 89, 92]. 

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-... 

Cholesterol makes up 17% of myelin and is present in plasma membranes. However, it usually does not occur in bacteria and is present only in trace amounts in mitochondria. Related sterols are present in plant membranes. Esters of sterols occur as transport forms but are not found in membranes. Membrane bilayers, likewise, contain little or no triacylglycerols, the latter being found largely as droplets in the cytoplasm. 

Until 1993 apolipoprotein E was best known for its central role in plasma lipoproteins and cholesterol transport (Fig. 21-1). However, one of the three common alleles of the apoE gene confers a significant risk of development of Alzheimer disease.12171218 A high blood cholesterol level is also correlated with increased risk.12191220 Membrane abnormalities in mitochondria have been associated with Alzheimer disease.1221 Also related to membranes and lipid metabolism, vitamin E appears to combat Alzheimer disease.843 1218... 

In addition to their plasma membrane eukaryotic cells also contain internal membranes that define a variety of organelles (fig. 17.2). Each of these organelles is specialized for particular functions The nucleus synthesizes nucleic acids, mitochondria oxidize carbohydrates and lipids and make ATP, chloroplasts carry out photosynthesis, the endoplasmic reticulum and the Golgi apparatus synthesize and secrete proteins, and lysosomes digest proteins. Additional membranes divide mitochondria and chloroplasts into even finer, more specialized subcompartments. Like the plasma membrane, organellar membranes act as barriers to the leakage of proteins, metabolites, and ions they contain transport systems for import and export of materials, and they are the sites of enzymatic activities as diverse as cholesterol biosynthesis and oxidative phosphorylation. 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

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.

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