Triacylglycerols transport into cells

Fatty acids Despite the fact that fatty acids are lipid soluble, so that they will diffuse across membranes without a transporter, one is present in the plasma membrane to speed up entry into the cells, so that it is sufficient to meet the demand for fatty acid oxidation. Triacylglycerol transport into cells also depends on the fatty acid transporter. Since it is too large to be transported per se, it is hydrolysed within the lumen of the capillaries in these tissues and the resultant fatty acids are taken up by the local cells via the fatty acid transporter (Chapter 7). Hence the fatty acid transporter molecule is essential for the uptake of triacylglycerol. 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

The chylomicrons are released into the lymph system and then into the blood. These particles bind to membrane-bound lipases, primarily at adipose tissue and muscle, where the triacylglycerols are once again degraded into free fatty acids and monoacylglycerol for transport into the tissue. The triacylglycerols are then resynthesized inside the cell and stored. In the muscle, they can be oxidized to provide energy. 

The triacylglycerols are emulsified in the small intestine by bile salts. They are then digested by lipases, the most important of which is pancreatic lipase. The products, fatty acids and monoacylglycerol, are transported into enterocytes and reconverted to triacylglycerol. Triacylglycerol is subsequently incorporated into chylomicrons, which are then transported into lymph via exocytosis and finally into the bloodstream for transport to the fat cells. 

Fig. 31.15. Glucose metabolism in various tissues. A. Effect of insulin on glycogen synthesis and degradation and on VLDL synthesis in the liver. B. Glucose metabolism in resting muscle in the fed state. The transport of glucose into cells and the synthesis of glycogen are stimulated by insulin. C. Glucose metabolism in adipose tissue in the fed state. FA = fatty acids DHAP = dihydroxyacetone phosphate. FA = fatty acids TG = triacylglycerols -I- = stimulated by insulin — = inhibited by insulin.

After entering the cytoplasm, the fatty acids are trapped in the cell via the action of thiokinase that yields fatty-acyl-CoA. The activated fatty acids are either oxidized after transport into the mitochondria or reesterified with glycerol to give triacylglycerols that are stored in lipid droplets in the cytoplasm. The esterification may be only partial, giving diacylglycerols that are intermediates in phospholipid synthesis. 

Medium-chain acyl-CoA synthetase, which is present within the mitochondrial matrix of the liver, activates fatty acids containing from four to ten carbon atoms. Medium-chain length fatty acids are obtained mainly from triacylglycerols in dairy products. However, unlike long-chain fatty acids, they are not esterified in the epithelial cells of the intestine but enter the hepatic portal vein as fatty acids to be transported to the liver. Within the liver, they enter the mitochondria directly, where they are converted to acyl-CoA, which can be fully oxidised and/or converted into ketone bodies. The latter are released and can be taken up and oxidised by tissues. 

The packaging of triacylglycerol into chylomicrons or VLDL provides an effective mass-transport system for fat. On a normal Western diet, approximately 400 g of triacylglycerol is transported through the blood each day. Since these two particles cannot cross the capillaries, their triacylglycerol is hydrolysed by lipoprotein lipase on the luminal surface of the capillaries (see above). Most of the fatty acids released by the lipase are taken up by the cells in which the lipase is catalytically active. Thus the fate of the fatty acid in the triacylglycerol in the blood depends upon which tissue possesses a catalytically active lipoprotein lipase. Three conditions are described (Figure 7.23) ... 

Sugar The hydrolysis of sucrose in the intestine produces both glucose and fructose, which are transported across the epithelial cells by specific carrier proteins. The fructose is taken up solely by the liver. Fructose is metabolised in the liver to the triose phosphates, dihydroxy-acetone and glycer-aldehyde phosphates. These can be converted either to glucose or to acetyl-CoA for lipid synthesis. In addition, they can be converted to glycerol 3-phosphate which is required for, and stimulates, esterification of fatty acids. The resulting triacylglycerol is incorporated into the VLDL which is then secreted. In this way, fructose increases the blood level of VLDL (Chapter 11). 

Most lipids are barely soluble in water, and many have amphipathic properties. In the blood, free triacylglycerols would coalesce into drops that could cause fat embolisms. By contrast, amphipathic lipids would be deposited in the blood cells membranes and would dissolve them. Special precautions are therefore needed for lipid transport in the blood. While long-chain fatty acids are bound to albumin and short-chain ones are dissolved in the plasma (see p. 276), other lipids are transported in lipoprotein complexes, of which there several types in the blood plasma, with different sizes and composition. 

VLDLs, IDLs, and LDLs are closely related to one another. VLDLs formed in the liver (see p. 312) transport triacylglycerols, cholesterol, and phospholipids to other tissues. Like chylomicrons, they are gradually converted into IDL and LDL under the influence of lipoprotein lipase [1]. This process is also stimulated by HDL. Cells that have a demand for cholesterol bind LDL through an interaction between their LDL receptor and ApoB-100, and then take up the complete particle through receptor-mediated endocytosis. This type of transport is mediated by depressions in the membrane ( coated pits"), the interior of which is lined with the protein clathrin. After LDL binding, clathrin promotes invagination of the pits and pinching off of vesicles ( coated vesicles"). The clathrin then dissociates off and is reused. After fusion of the vesicle with ly-sosomes, the LDL particles are broken down (see p. 234), and cholesterol and other lipids are used by the cells. 

The plasma lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglyc-erol and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid core (containing triacylglycerol, cholesteryl esters, or both) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily, triacylglycerol) plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs, thus making the chylomicrons functional. Apo C-ll activates lipoprotein lipase, which degrades the... 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

In summary, triacylglycerols from the diet are digested by lipase and associate with bile salts into mixed micelles. The free fatty acids are absorbed by the cells of the small intestine, from which they are transported via the lymph system to the liver. From the liver, they are released as apolipoproteins in the circulation, carrying fatty acids and cholesterol to the cells throughout the body. 

The newly synthesized triacylglycerol becomes organized into chylomicrons (a type of lipoprotein see next section), which are secreted by the intestinal epithelial cell into the lacteals, small lymph vessels in the villi of the small intestine. Then from the lymphatics, the chylomicrons pass into the thoracic duct, from which they enter the blood and thus contribute to the transport of lipid fuel to various tissues. A feature of chylomicron metabolism is their ability to deliver lipid fuels to extrahepatic tissues. 

In mammals, the major site of accumulation of triacylglycerols is the cytoplasm of adipose cells (fat cells). Droplets of triacylglycerol coalesce to form a large globule, which may occupy most of the cell volume (see Figure 22.1). Adipose cells are specialized for the synthesis and storage of triacylglycerols and for their mobilization into fuel molecules that are transported to other tissues by the blood. 

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. 

The fatty acids and monoacylglycerol are absorbed by the intestinal cells, converted to fatty acyl CoA and reassembled into triacylglycerols. The triacyl glycerols then assemble with phospholipids and lipoproteins to form chylomicrons for transport through the lymph and blood to the tissues. 

About 80% of the cholesterol synthesized in the liver is converted into bile salts. The remainder of the cholesterol, triacylglycerols, other lipids, and hydrophobic substances (including xenobiotics) are transported to other tissues throughout the body by plasma lipoproteins. These lipoproteins, which are classified according to density, consist of apoproteins (also made by the liver) and various combinations of fat and fat-soluble compounds. The liver also stores vitamins, especially vitamin A but also vitamins D, E and K, as well as vitamin B12, in fatstoring Ito cells, located between endothelial cells and hepatocytes. 

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. 

Much of the glucose not taken up by liver and muscle is taken up by adipocytes under the influence of insulin-stimulated transport of glucose into the cell. Esterification of fatty acids for storage as triacylglycerols is dependent on the availability of... 

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