Phospholipid transfer protein mechanism

Phospholipid transfer protein is a plasma protein that promotes the transfer of phospholipids down a phospholipid concentration gradient, probably by a shuttle mechanism... 

Phospholipid transfer protein (PLTP) (carrier protein that shuttles between lipoproteins to redistribute lipids) deficiency in mice is associated with decreased atherosclerosis despite decreased HDL levels. Two mechanisms are involved decreased Apo B-containing lipoprotein production and levels, and increased antioxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, DM, and CAD (reviewed in ref. 429). PLTP mRNA protein expression and activity was increased by cholesterol loading of macrophages. PLTP increased HDL binding to biglycan, suggesting a role in lipoprotein retention on ECM (430). 

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],... 

Two mechanisms have been proposed to explain the transport of phospholipids from the ER to other cellular membranes protein-mediated transfer and a vesicular process. Several experiments have demonstrated that water-soluble proteins, known as phospholipid exchange proteins, can bind to specific phospholipid molecules and transfer them to another bilayer. Vesicular transport of phospholipids and membrane proteins in structures known as transition vesicles from the ER to the Golgi complex is not clearly understood. However, evidence of transfer of luminal material from the ER to the Golgi cistemae clearly supports vesicular transport. 

Membrane phospholipids are synthesized on the cytoplasmic side of SER membrane. Because the polar head groups of phospholipid molecules make transport across the hydrophobic core of a membrane an unlikely event, a translocation mechanism is used to transfer phospholipids across the membrane to ensure balanced growth. Choline-containing phospholipids are found in high concentration on the lumenal side of ER membrane because a prominent phospholipid translocator protein called flippase preferentially transfers this class of molecule. 

Since lipid transfer proteins were demonstrated, it will be essential to demonstrate the common route of Apo C and phospholipids (with a specificity for each Apo C), when VLDL undergo lipolysis. The mechanism of Apo C transfer from HDL to triglyceride-rich lipoproteins (VLDL or chylomicrons) remains obscure. 

The mechanisms involved in the establishment of lipid asymmetry are not well understood. The enzymes involved in the synthesis of phospholipids are located on the cytoplasmic side of microsomal membrane vesicles. Translocases (flippases) exist that transfer certain phospholipids (eg, phosphatidylcholine) from the inner to the outer leaflet. Specific proteins that preferentially bind individual phospholipids also appear to be... 

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]. 

Figure 18-16 depicts a model for the selective uptake of cholesteryl esters by a cell-surface receptor called SR-BI (scavenger receptor, class B, type I). SR-BI binds HDL, LDL, and VLDL and can mediate selective uptake from all of these lipoproteins. The detailed mechanism of selective llpid uptake has not yet been elucidated, but It may entail hemifuslon of the outer phospholipid monolayer of the lipoprotein and the exoplasmic leaflet of the plasma membrane. The cholesteryl esters Initially enter the hydrophobic center of the plasma membrane, are subsequently transferred across the Inner leaflet, and are eventually hydrolyzed by cytosolic, not lysosomal, cholesteryl esterases. The llpid-depleted particles remaining after llpid transfer dissociate from SR-BI and return to the circulation they can then extract more phospholipid and cholesterol from other cells by means of the ABCAl protein or other cell-surface transport proteins (see Figure 18-13c). Eventually, small llpid-depleted HDL particles circulating In the bloodstream are filtered out by the kidney and bind to a different receptor on renal epithelial cells. After these particles have been Internalized by receptor-mediated endocytosis, they are degraded by lysosomes.

Electron transport systems perform important functions concerning respiration and energy metabolism in eucaryotes [22, 23], The electron transport reactions occur at the mitochondria inner membrane formed by electron transport proteins [24] and the lipid bilayer built up by the self-assembly of phospholipids as vital smfactants [25, 26]. The electron transport proteins include redox catalysts such as nicotinamide, iron [27, 28], and quinones [29]. The electrons produced by these redox reactions transfer through the lipid bilayer. While the relationship between the electron transport mechanisms and the molecular self-assembly in vivo has been clarified, control of the self-assembly by electron transport has been applied for an artificial polymeric surfactant. 

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