Free Fatty Acids Are Rapidly Metabolized

The free fatty acids (FFA, nonesterified fatty acids, un-esterified fatty acids) arise in the plasma from lipolysis of triacylglycerol in adipose tissue or as a result of the action of lipoprotein lipase during uptake of plasma tri-acylglycerols into tissues. They are found in combination with albumin, a very effective solubilizer, in concentrations varying between 0.1 and 2.0 |eq/mL of plasma. Levels are low in the fully fed condition and rise to 0.7-0.8 | eq/mL in the starved state. In uncontrolled diabetes mellitus, the level may rise to as much as 2 | eq/mL.

Peripheral apoprotein (eg, apo C)

Peripheral apoprotein (eg, apo C)

Generalized Lipoprotein Structure
Figure 25-1. Generalized structure of a plasma lipoprotein. The similarities with the structure of the plasma membrane are to be noted. Small amounts of cholesteryl ester and triacylglycerol are to be found in the surface layer and a little free cholesterol in the core.

Free fatty acids are removed from the blood extremely rapidly and oxidized (fulfilling 25-50% of energy requirements in starvation) or esterified to form triacylglycerol in the tissues. In starvation, esterified lipids from the circulation or in the tissues are oxidized as well, particularly in heart and skeletal muscle cells, where considerable stores of lipid are to be found.

The free fatty acid uptake by tissues is related directly to the plasma free fatty acid concentration, which in turn is determined by the rate of lipolysis in adipose tissue. After dissociation of the fatty acid-albumin complex at the plasma membrane, fatty acids bind to a membrane fatty acid transport protein that acts as a transmembrane cotransporter with Na+. On entering the cytosol, free fatty acids are bound by intracellular fatty acid-binding proteins. The role of these proteins in intracellular transport is thought to be similar to that of serum albumin in extracellular transport of long-chain fatty acids.

TRIACYLGLYCEROL IS TRANSPORTED FROM THE INTESTINES IN CHYLOMICRONS & FROM THE LIVER IN VERY LOW DENSITY LIPOPROTEINS

By definition, chylomicrons are found in chyle formed only by the lymphatic system draining the intestine. They are responsible for the transport of all dietary lipids into the circulation. Small quantities of VLDL

are also to be found in chyle; however, most of the plasma VLDL are of hepatic origin. They are the vehicles of transport of triacylglycerol from the liver to the extrahepatic tissues.

There are striking similarities in the mechanisms of formation of chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells (Figure 25-2), perhaps because—apart from the mammary gland—the intestine and liver are the only tissues from which par-ticulate lipid is secreted. Newly secreted or "nascent" chylomicrons and VLDL contain only a small amount of apolipoproteins C and E, and the full complement is acquired from HDL in the circulation (Figures 25-3 and 25-4). Apo B is essential for chylomicron and VLDL formation. In abetalipoproteinemia (a rare disease), lipoproteins containing apo B are not formed and lipid droplets accumulate in the intestine and liver.

A more detailed account of the factors controlling hepatic VLDL secretion is given below.

CHYLOMICRONS & VERY LOW DENSITY LIPOPROTEINS ARE RAPIDLY CATABOLIZED

The clearance of labeled chylomicrons from the blood is rapid, the half-time of disappearance being under 1 hour in humans. Larger particles are catabolized more quickly than smaller ones. Fatty acids originating from chylomicron triacylglycerol are delivered mainly to adipose tissue, heart, and muscle (80%), while about 20% goes to the liver. However, the liver does not metabolize native chylomicrons or VLDL significantly; thus, the fatty acids in the liver must be secondary to their metabolism in extrahepatic tissues.

Triacylglycerols of Chylomicrons & VLDL Are Hydrolyzed by Lipoprotein Lipase

Lipoprotein lipase is located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of heparan sulfate. It has been found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland, though it is not active in adult liver. It is not normally found in blood; however, following injection of heparin, lipoprotein lipase is released from its hep-aran sulfate binding into the circulation. Hepatic li-pase is bound to the sinusoidal surface of liver cells and is released by heparin. This enzyme, however, does not react readily with chylomicrons or VLDL but is concerned with chylomicron remnant and HDL metabolism.

Both phospholipids and apo C-II are required as cofactors for lipoprotein lipase activity, while apo A-II

Figure25-2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum; G, Golgi apparatus; N, nucleus; C, chylomicrons; VLDL, very low density lipoproteins; E, endothelium; SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

Role Rer Chylomicron Synthesis

Figure25-2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum; G, Golgi apparatus; N, nucleus; C, chylomicrons; VLDL, very low density lipoproteins; E, endothelium; SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

and apo C-III act as inhibitors. Hydrolysis takes place while the lipoproteins are attached to the enzyme on the endothelium. Triacylglycerol is hydrolyzed progressively through a diacylglycerol to a monoacylglycerol that is finally hydrolyzed to free fatty acid plus glycerol. Some of the released free fatty acids return to the circulation, attached to albumin, but the bulk is transported into the tissue (Figures 25-3 and 25-4). Heart lipoprotein lipase has a low Km for triacylglycerol, about one-tenth of that for the enzyme in adipose tissue. This enables the delivery of fatty acids from triacylglycerol to be redirected from adipose tissue to the heart in the starved state when the plasma triacylglycerol decreases. A similar redirection to the mammary gland occurs during lactation, allowing uptake of lipoprotein triacyl-glycerol fatty acid for milk fat synthesis. The VLDL receptor plays an important part in the delivery of fatty acids from VLDL triacylglycerol to adipocytes by binding VLDL and bringing it into close contact with lipoprotein lipase. In adipose tissue, insulin enhances lipoprotein lipase synthesis in adipocytes and its translocation to the luminal surface of the capillary en-dothelium.

The Action of Lipoprotein Lipase Forms Remnant Lipoproteins

Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons and in the loss of apo C (which returns to HDL) but not apo E, which is retained. The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol (Figure 25-3). Similar changes occur to VLDL, with the formation of VLDL remnants or IDL (intermediate-density lipoprotein) (Figure 25-4).

The Liver Is Responsible for the Uptake of Remnant Lipoproteins

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-100, E) receptor and the LRP (LDL receptor-related protein)

Dietary TG

Dietary TG

Liver Metabolism Amino Acids

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; ©, apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant lipids are shown.

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; ©, apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant lipids are shown.

are believed to take part. Hepatic lipase has a dual role: (1) in acting as a ligand to the lipoprotein and (2) in hydrolyzing its triacylglycerol and phospholipid.

VLDL is the precursor of IDL, which is then converted to LDL. Only one molecule of apo B-100 is present in each of these lipoprotein particles, and this is conserved during the transformations. Thus, each LDL particle is derived from only one VLDL particle (Figure 25-4). Two possible fates await IDL. It can be taken up by the liver directly via the LDL (apo B-100, E) receptor, or it is converted to LDL. In humans, a relatively large proportion forms LDL, accounting for the increased concentrations of LDL in humans compared with many other mammals.

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