Lipid Metabolism

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Triacylglycerols (fats, triglycerides) constitute 90% of dietary lipid, and are the major form of energy storage in humans. The structure of triglycerides has been shown before (See Figure 10.2). Oxidative metabolism of fats yields more than twice the energy as an equal weight of dry carbohydrate or protein. Remember that fats are insoluble in water. Digestive enzymes, however, are water soluble. Digestion of fats must therefore take place at the interface where fat meets water. Obviously more digestion can occur if more surface area is exposed. Two things act in this regard to aid fat digestion - 1) motion of the intestine (See Figure 18.3 ) and 2) bile acids (secreted by the liver), which act as "digestive detergents" to emulsify fats (See Figure 18.4 ).

Overview of Lipid Metabolism

Figure 18.1 depicts lipid metabolism relative to the rest of intermediary metabolism.

Fat Digestion/Absorption

Triacylglycerols in the body are derived primarily from:

Pancreatic Lipase acts to hydrolyze triacylglycerols at positions 1 (last point of hydrolysis) and 3 (first point of hydrolysis). The products of this reaction are Na+ and K+ salts of fatty acids (also known as soaps). Soaps, of course, help emulsify fats. Further, the activity of pancreatic lipase actually increases when it contacts the lipid-water interface (interfacial activation). Binding of pancreatic lipase to the lipid-water interface requires a complex with another factor, pancreatic colipase. In the absence of substrate (lipids), the enzyme complex's active site is buried by a lid-like structure. In the present of lipid, the active site is exposed and in the process a hydrophobic entrance to the active site is exposed.

Remember that a micelle is formed when soaps surround a non-polar substance in water. Lipid digestion by pancreatic lipases generates mono and diacylglycerols that are absorbed in the small intestine. Bile acids aid in this process too, forming micelles. Blocked bile ducts inhibit absorption of fats considerably. Remember also that vitamins A,D,E, and K are fat soluble, and their absorption too is dependent on bile acids. Once inside the intestinal cells, fatty acids complex with a protein in the cytoplasm called intestinal fatty acid-binding protein (I-FABP) that increases their effective solubility and protects the cell from their detergent effects.

Packing into Chylomicrons

The mono and diacylglycerols in the digestive cells are converted back to triglycerides, and packaged into lipoproteins in the bloodstream called chylomicrons (See Figure 18.3). They travel into the blood stream via the lymph system. Triacylglycerols are also synthesized by the liver where they are packaged as very low density lipoproteins (VLDLs) and released into the blood. Upon arrival in adipose tissue and muscle cells, lipoprotein lipase cleaves them to free fatty acids and glycerol. Fatty acids are taken up by these tissues and glycerol is transported to liver or kidneys where it is converted to dihydroxyacetone phosphate (glycolysis intermediate) by glycerol kinase (puts phosphate on) and glycerol-3-phosphate dehydrogenase (oxidizes to DHAP).

In adipose tissue, hydrolysis of fats to fatty acids and glycerol is accomplished by hormone-sensitive triacylglycerol lipase. Free fatty acids are released there into the blood stream where they bind to albumin.

Lipoproteins

Lipoprotein complexes carry lipids in the bloodstream (See Figure 18.5). Very little free lipid can be detected in the blood. The protein components of the lipoproteins are synthesized in the liver and intestinal mucosa cells. Classes of lipoproteins and their properties are shown in Table 18.1. Lipoproteins form micelles with lipids as a mechanism of transporting them in the aqueous environment of the blood. The five categories of lipoproteins are summarized below:

Chylomicrons - assemble in intestinal mucosa, carry exogenous fats and cholesterol via lymph system to large body veins (See Figure 18.7). Chylomicrons adhere to inner surface of capillaries of skeletal muscle and adipose tissue (fat cells) (See Figure 18.6). Fats contained within them (but not cholesterol) are hydrolyzed by lipoprotein lipase, freeing fatty acids and monoacylglycerol. The remaining shrunken chylomicron structure is called a chylomicron remnant, which contains cholesterol and dissociates from the capillary endothelium and reenters the circulation system where it is taken up by the liver. Thus, chylomicrons deliver dietary fats to muscle and adipose tissue. They also carry dietary cholesterol to the liver.

VLDL - VLDLs are synthesized by the liver and, like chylomicrons, are degraded by lipoprotein lipase. VLDL, IDL, and LDL are interrelated. IDL and LDL appear in the circulation as VLDL remnants. VLDL is converted to LDL by removal of all proteins except apo B-100 and esterification of most of the cholesterol by lecithin-cholesterol acyl transferase (LCAT) associated with HDLs. The esterification occurs by transfer of a fatty acid from lecithin to cholesterol (forming lysolecithin).

The protein components of lipoproteins are called apolipoproteins (or apoproteins). These proteins, though water soluble, have a hydrophobic and a hydrophilic character that is apparent in their alpha helices. Their alpha helical regions are stabilized upon incorporation into lipoproteins. The lipids appear to stabilize the helices because they are composed of hydrophobic amino acids on one side of the helix (facing the lipid) and hydrophilic amino acids on the other (facing water). Nine apolipoproteins common in humans are summarized in Table 18.2.

Cholesterol Uptake

Cholesterol makes it to animal cell membranes by either external transfer, or by cellular synthesis (See Figure 18.7) Exogenous cholesterol reaches cells from LDL. LDL binds to cellular LDL receptor, a transmembrane glycoprotein that binds both ApoB-100 and apoE. LDL receptors form clusters of "coated pits" (See Figure 18.9). Clathrin, the scaffolding protein of the coated vesicles that transfer proteins between RER and the Golgi apparatus, forms the backing of the coated pits. The coated pits invaginate into the plasma membrane, forming coated vesicles that fuse with lysosomes. This process is known as receptor mediated endocytosis (see Figure 18.8). Inside the lysosome, cholesteryl esters are hydrolyzed, yielding free cholesterol, which can be incorporated into cell membranes. Excess cholesterol is reesterified for storage. (See Figure 18.10).

Interestingly, high intracellular cholesterol suppresses synthesis of LDL receptor and biosynthesis of cholesterol, two factors that prevent overaccumulation of cholesterol in cells.

HDL Transports Cholesterol from Tissues to the Liver

HDL removes cholesterol from tissues and transports it to the liver. HDL is created mostly from components from other degraded lipoproteins. HDL converts cholesterol to cholesteryl esters by LCAT, an enzyme activated by apoA-I in HDL. HDL appears to get cholesterol to the liver 1) by transfer of the cholesteryl ester to VLDL which after degradation to IDL and LDL is taken to the liver and 2) by direct interactions between HDL and the liver via a specific HDL receptor. The liver disposes of cholesterol as bile acids. HDL is also called "good cholesterol" because it is associated with lowering cholesterol levels.

Lipoprotein Dysfunction in Atherosclerosis

Development of atherosclerosis is strongly correlated with the level of plasma cholesterol. Individuals with familial hypercholesterolemia (FH) have high levels of LDL and plasma cholesterol levels 3-5 times higher than the average level. People homozygous for the disease often die from myocardial infarction at ages as early as 5. Cells taken from these people completely lack functional LDL receptors. The high levels of plasma LDL is due to 1) decreased degradation of LDL, since there are no receptors to take them up, and 2) increased synthesis of IDL due to the lack of LDL receptors to take up IDL. Macrophages from FH homozygous individuals contain macrophages ( a type of white blood cell) so full of cholesterol they are called foam cells. Macrophages readily take up LDL that has been acetylated at Lys residues. This has the effect of increasing LDL's negative charge. A receptor on the macrophage called the scavenger receptor normally binds oxidized LDL as well as polyanionic molecules (molecules with many negative charges). LDL has many unsaturated fatty acids that are highly susceptible to chemical oxidation. Normally they are protected by antioxidants, but these become depleted when LDL is trapped within artery walls. When this happens, oxygen radicals oxidize the LDL fatty acids to aldehydes and oxides which react with Lys residues, like an acetylation reaction. Binding of macrophages to LDL results in its uptake of cholesterol and, ultimately to the formation of foam cells. Antioxidants prevent atherorsclerosis in rabbits. Cigarette smoke oxidizes LDL also.

"Good Cholesterol"

High plasma HDL levels are strongly correlated with a low incidence of cardiovascular disease. Cigarette smoking is inversely correlated to HDL concentrations, but exercise, alcohol, weight loss, and estrogens are linked to higher HDL levels. There is an inverse correlation in humans between risk of atherosclerosis and plasma level of apoA-I, the major protein component of HDL. Cholesterol ester transfer protein (CETP) mediates transfer of cholesteryl esters from HDL to VLDL and LDL. Animals that express CETP have higher cholesterol levels in their VLDL and LDL and lower cholesterol levels in HDL than animals that do not express CETP Making animals that do not have CETP transgenic to express the protein developed atherosclerotic lesions more rapidly on a high fat diet than non-transgenic animals fed the same diet.

Diet and Cholesterol Metabolism

A diet rich in saturated fatty acids is associated with high plasma cholestero levels. Diets rich in polyunsaturated fatty acids produce decreased cholesterol levels. Consumption of fatty acids called n-3 (or omega-3) fatty acids that are abundant in fish oils dramatically lowers serum cholesterol and triglyceride levels.

Fat Mobilization

Energy stored in fats is released after the digestion of the fat begins. An enzyme catalyzing this initial stage is called Triacylglycerol Lipase (or hormone sensitive lipase). Its action is shown in the figure on page 631. Fatty acids released by the enzyme enter the bloodstream and become bound to albumin. Glycerol released byfat digestion is exported to the liver. A part of the cAMP cascade is involved in activation of Triacylglycerol Lipase, as shown in Figure 18.11.