Endoplasmic reticulum cholesterol transport

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

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... 

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]. 

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. 

Lipoproteins Are Made in the Endoplasmic Reticulum of the Liver and Intestine Chylomicrons and Very-Low-Density Lipoproteins (VLDLs) Transport Cholesterol and Triacylglycerol to Other Tissues Low-Density Lipoproteins (LDLs) Are Removed from the Plasma by the Liver, Adrenals, and Adipose Tissue... 

The transport of cholesterol to, and its side-chain cleavage in, the mitochondria are the most important steps in the hormonal control of steroidogenesis. The enzymatic activities in the endoplasmic reticulum are also under hormonal control. However, expression of hormonal effects in this compartment requires several hours and is therefore part of the chronic, trophic effects of LH [3,4,32],... 

Critical to vitamin D3 action is its further metabolic conversion to more active compounds (Figure 1.3). Via its transport by DBP, vitamin D3 accumulates in the liver [48]. In rats, as much as 60-80% of an injected or oral dose of vitamin D3 locates to the liver [49-51], Intestinal absorption of vitamin D3 is in association with the chylomicron fraction via the lymphatic system. Vitamin D3 is delivered to the liver in blood from the thoracic duct only a few hours post ingestion [44], A specific portion of hepatic vitamin D3 in the rat is converted to 25-OH-D3 by a 25-hydroxylase system in the endoplasmic reticulum of hepatocytes [52, 53]. This enzyme (Km 10"8 M) is regulated to an extent by 25-OH-D3 and its metabolites. Higher concentrations of vitamin D3 are handled by a second 25-hydroxylase located in liver mitochondria [54], This enzyme, also known as CYP27, 27-hydroxylates cholesterol and thus appears less discriminating than the microsomal 25-OHase which does not use cholesterol as substrate [55, 56]. In humans, however,... 

Fig. 8.4 The function of caveolae . On the left once the caveolae have arrived In the membrane, they begin to transport cholesterol and other lipids from the endoplasmic reticulum to the plasma membrane and back (shown on the right). (Reproduced from Rg. 3. in ref. 26, with permission of the author and Annu Rev. Biochem.)...

In this autosomal recessive disease, the disorder does not involve the gene on chromosome 2, which is responsible for apoprotein assembly, but the MTP gene (microsomal triglyceride transfer protein), which is localized on chromosome 4 q 22—24. In the endoplasmic reticulum, MTP transfers cholesterol esters, triglycerides and phospholipids to the nascent apoprotein B. This process is a prerequisite for the transport of the complete lipoproteins (e.g. chylomicrons, VLDL) to the Golgi complex and their secretion into the blood via subsequent exocytosis. In the case of MTP deficiency, lipoprotein particles are not secreted, with the result that any superfluous apoprotein B is broken down in the endoplasmic reticulum. (214, 216, 219, 220)... 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

After partial hydrolysis in the gut, dietary fatty acids, monoacylglycerols, phospholipids, and cholesterol are absorbed into the mucosal enterocytes lining the small intestine (Chapter 12). Once within the cell, the lipids are reesterified and form a lipid droplet within the lumen of the smooth endoplasmic reticulum. These droplets consists of triacylglycerol and small amounts of cholesteryl esters and are stabilized by a surface film of phospholipid. At the junction of the smooth and the rough endoplasmic reticulum, the droplet acquires apoproteins B-48, A-I, A-II, and A-IV, which are produced in the lumen of the rough endoplasmic reticulum in the same way as other proteins bound for export. The lipoprotein particle is then transported to the Golgi stacks where further processing yields chylomicrons, which are secreted into the lymph and then enter the blood circulation at the thoracic duct. 

A FIGURE 18-1 Overview of synthesis of major membrane lipids and their movement into and out of cells. Membrane lipids (e.g., phospholipids, cholesterol) are synthesized through complex multienzyme pathways that begin with sets of water-soluble enzymes and intermediates in the cytosol (D) that are then converted by membrane-associated enzymes into water-insoluble products embedded in the membrane (B), usually at the interface between the cytosolic leaflet of the endoplasmic reticulum (ER) and the cytosol. Membrane lipids can move from the ER to other organelles (H), such as the Golgi apparatus or the mitochondrion, by either vesicle-mediated or other poorly defined mechanisms. Lipids can move into or out of cells by plasma-membrane transport proteins or by lipoproteins. Transport proteins similar to those described in Chapter 7 that move lipids (0) include sodium-coupled symporters that mediate import CD36 and SR-BI superfamily proteins that can mediate... 

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