Cholesterol, lipoprotein transport

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

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. 

CHOLESTEROL IS TRANSPORTED BETWEEN TISSUES IN PLASMA LIPOPROTEINS (Figure 26-6)... 

Triglycerides and cholesterol are transported in the blood as lipoproteins. Lipoproteins are named according to their density, which increases with the percentage of protein in the particle. From least dense to most dense ... 

Lipoproteins are an important class of serum proteins in which a spherical hydrophobic core of triglycerides or cholesterol esters is surrounded by an amphipathic monolayer of phospholipids, cholesterol and apolipoproteins (fatbinding proteins). Lipoproteins transport lipid in the circulation and vary in size and density, depending on their proteindipid ratio (Figure 7.3). Lipoprotein metabolism is adversely affected by obesity low-density lipoprotein (LDL)-cholesterol and plasma triglyceride are increased, together with decreased high-density lipoprotein (HDL)-cholesterol concentrations. 

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. 

Plasma cholesterol may arise from the diet or from endogenous biosynthesis. In either case, cholesterol is transported between tie tissues in combination with protein and phospholipids as lipoproteins. 

The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquire cholesterol from peripheral tissues in a pathway that protects the cholesterol homeostasis of cells. In this process, free cholesterol is transported from the cell membrane by a transporter protein, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not endocytose the lipoproteins. 

Cholesterol is an essential component of cellular membranes. In addition to dietary sources, we can also synthesize cholesterol. Cholesterol is transported in the blood as a lipoprotein, which is an aggregate of water-soluble proteins, cholesterol, and other lipids, including triglycerides. Proteins are denser than lipids,... 

Cholesterol can be obtained either from the diet or it can be synthesized de novo, mainly in the liver. Cholesterol is transported round the body in lipoprotein particles (see Topic K6). The rate of synthesis of cholesterol is dependent on the cellular level of cholesterol. High levels of cholesterol and its metabolites control cholesterol biosynthesis by ... 

Cholesterol is an extremely important biological molecule that modulates the fluidity of animal cell membranes and is the precursor of steroid hormones (such as progesterone, testosterone, oestradiol and cortisol) and bile acids. Cholesterol is either derived from the diet or synthesised de novo. Regardless of the source, cholesterol is transported through the circulation in lipoprotein particles, as are cholesterol esters, the cellular storage form of cholesterol. The amount of cholesterol synthesised daily in the liver of a normal person is usually double that obtained from dietary sources. Other sites of cholesterol synthesis include the intestine, and the degree of production is highly responsive to cellular levels of cholesterol. Over 1.2 g of cholesterol is lost in the faeces daily in the form of free sterol or as bile acids. 

The substance itself isn t soluble in water or, on a more practical level, in the bloodstream. So cholesterol is transported through the body in a variety of envelopes made of fat and protein called lipoproteins. Cholesterol transported in a low-density lipoprotein envelope tends to be deposited in damaged regions of our arteries. That s a bad thing, so we call LDL (low-density lipoprotein) cholesterol bad. But in the body s system of balances, we also have cholesterol transported out of those arteries and removed from the bloodstream by HDL (high-density lipoprotein). We call that combination the good cholesterol. 

LDL particles (low density lipoproteins) transport cholesterol from the liver to the tissues. 

In the intestinal mucosal cells, the triacylglycerols are resynthesized from fatty acids and monoacylglycerols and then packaged into lipoprotein transport particles called chylomicrons, stable particles ranging from approximately 180 to 500 nm in diameter (Figure 22.5). These particles are composed mainly of triacylglycerols, with apoprotein B-48 as the main protein component. Protein constituents of lipoprotein particles are called apolipoproteins. Chylomicrons also function in the transport of fat-soluble vitamins and cholesterol. 

Lipoproteins Transport Cholesterol and Triacylglycerols Throughout the Organism... 

The quantity of cholesterol transported from the liver to peripheral tissues greatly exceeds its catabolism there and mechanisms exist to return cholesterol to the liver. Through this reverse transport, cholesterol is carried by high-density lipoprotein (HDL) from peripheral cells to the liver where it is taken up by a process involving hepatic lipase. Cholesterol in the plasma is also recycled to LDL and VLDL by cholesterol-ester transport protein (CETP). 

Cholesterol is transported to and from the cells by special carriers called lipoproteins. There are two types, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). It is believed that excess LDL cholesterol can clog arteries, increasing risk of heart attack and stroke. Conversely, studies suggest that higher levels of HDL cholesterol reduce risk of heart attack. That is, the ratio of LDL to HDL appears to be important. The adverse effects of a prolonged (i.e., chronic) history of excess LDL relative to HDL is of much greater concern than acute exposures to cholesterol. 

Although the term lipoprotein can describe any protein that is covalently linked to lipid groups (e.g., fatty acids or prenyl groups), it is most often used for a group of molecular complexes found in the blood plasma of mammals (especially humans). Plasma lipoproteins transport lipid molecules (triacylglycerols, phospholipids, and cholesterol) through the bloodstream from one organ to another. Lipoproteins also contain several types of lipid-soluble antioxidant molecules (e.g., a-tocopherol and several carotenoids). (The function of antioxidants, substances that protect biomolecules from free radicals, is described in Chapter 10.) The protein components of lipoproteins are called apolipoproteins or apoproteins. 

CE = cholesterol esters TG = triglycerides LPL = lipoprotein lipase FFA = free fatty acids apo CD cofactor for LPL apoAl = cofactor for LCAT LCAT = lecithin cholesterol acetyl transferase CETP = cholesterol ester transport protein... 

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... 

Lipids do not dissolve easily in water. Therefore, they have to be transported in blood as lipoproteins. Lipoproteins are formed from a protein envelope, made of apoprotein, containing a variable mix of triglycerides and cholesterol. Lipoproteins vary in size, weight and density. Eigure 4.8 shows a simplified version of lipid metabolism. 

Low-density lipoproteins (LDLs) are medium sized and rich in cholesterol. They transport lipids to any cell that needs them. Cell membranes have LDL receptors to which LDLs attach prior to being taken into the cell. The LDLs are broken down in the cell, the lipids used and the receptors temporarily disappear. Any excess LDLs in the circulation are of a size to deposit cholesterol in the walls of damaged arteries. High levels of circulating LDLs are associated with the development of atherosclerosis. 

Plasma lipoproteins are complex lipids that transport other lipids through the bloodstream. Chylomicrons carry dietary triglycerides from the intestine to other tissues. Very low density lipoproteins carry triglycerides synthesized in the liver to other tissues for storage. Low-density lipoproteins carry cholesterol to peripheral tissues and help regulate blood cholesterol levels. High-density lipoproteins transport cholesterol from peripheral tissues to the liver. 

The hydrophobic, water-insoluble cholesterol is transported in blood to cells predominantly as part of high density and low density lipoprotein particles (HDLs and LDLs, respectively). LDLs transport cholesterol to ex-trahepatic tissues. The LDL particles bind to LDL receptors on the cell... 

Hydrolysis of fats in capillaries by lipoprotein lipase yields intermediate-density lipoproteins (IDLs) from VLDLs and chylomicron remnants from chylomicrons (Figure 18.7). IDLs are taken up by the liver and further processed to low-density lipoproteins (LDLs). LDLs are the primary form by which cholesterol is transported to tissues and high-density lipoproteins (HDLs) serve to transport cholesterol from tissues back to the liver. 

Low-Density Lipoprotein (LDL) - LDLs are produced by the liver and are the principal form in which cholesterol is transported to tissues (Figures 18.7,18.10). More than 50% of the weight of the LDL particle is composed of cholesterol esters and free cholesterol. 

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