Lipids Core Notes (Series 1) PDF

BIOENERGETICS AND INTEGRATED METABOLISM LIPID METABOLISM Discipline of Biochemistry (Westville Campus) 1 Lipids play roles both in energy metabolism and in aspects of biological structure and function. The great bulk of lipid in most organisms...

BIOENERGETICS AND INTEGRATED METABOLISM LIPID METABOLISM Discipline of Biochemistry (Westville Campus) 1 Lipids play roles both in energy metabolism and in aspects of biological structure and function. The great bulk of lipid in most organisms is in the form of triacylglycerols (triglycerides). A mammal may contain 5-25% of its body weight as lipid and 90% of this in the form of triacylglycerols. Most of this fat, is stored in adipose tissue. Triacylglycerols are derived from 2 primary sources: a) the diet-digestion, absorption, and transport of fats to adipose tissue b) mobilization of fat stored in adipocytes. 1) DIGESTION OF DIETARY FATS An adult man ingests about 60-100g of fat per day. Triacylglycerides constitute more than 90% of the dietary fat. The rest is made up of phospholipids, cholesterol, cholesterol esters, and free fatty acids. · Lipids are soluble in organic solvents. Conversely, they are sparingly or not at all soluble in aqueous solutions. This poor water solubility presents problems for digestion because the substrates are not easily accessib1e to the digestive enzymes in the aqueous phase. In addition, even if ingested lipids are hydrolysed into simple constituents, the products tend to aggregate to larger complexes that make poor contact with the cell surface and therefore are not easily absorbed. These problems are overcome by i) increases in the interracial area between the aqueous and lipid phase and ii) ‘solubilization’ of the hydrolysis products with detergents. Essential to the normal digestion and intestinal absorption of lipids are bile salts, detergent substances secreted from the gallbladder. These are salts of bile acids such as cholic and chenodeoxycholic acid which are synthesized in hepatocytes (liver cells) from cholesterol. These bile acids are composed of 24 carbon atoms containing 2 or 3 hydroxyl groups. They have a side chain that ends in a carboxyl group that is ionized at pH 7.0. The carboxyl group of the primary bile acids is often conjugated via an amide bond to either glycine (NH2-CH- COOH) or taurine (NH2-CH2-CH2-S0 3H) to form glycocholic or taurocholic acid respectively and constitute the forms that are secreted into bile. 2 A bile salt molecule contains a hydrophobic surface and a hydrophilic surface. This characteristic allows bile salts to dissolve at an oil-water interface, with the hydrophobic surface in contact with a polar phase and the hydrophilic surface in contact with the aqueous phase. This detergent action emulsifies triacylglycerol to form particles approximately l µm in diameter yielding micelles, which allow digestive attack by water-soluble enzymes e.g. pancreatic lipase and facilitates the absorption of lipid through the intestinal mucosa. Figure 1: Action of bile salts in emulsifying fats in the intestine. The digestion of triacylglycerol occurs mainly in the duodenum of the small intestine into which flow both bile and the secretion of the pancreas. Pancreatic lipase hydrolyses ester links in the 1 and 3 positions of the triacylglycerol to yield the 2 monoacylglycerol and fatty acids: 3 The products of triacylglycerol digestion, mainly monoacylglycerol and long chain fatty acids must form a stable interaction with water before uptake and absorption into the epithelium of the intestine can occur. This stabilization is achieved by the action of the bile salts present in bile salts micelles. These bile salt micelles incorporate monoacylglycerols, lysophosphoglycerols and long chain fatty acids to form 'mixed' micelles. The mixed micelle formation conveys, the non-polar lipid molecules through the aqueous contents of the intestinal lumen, to the epithelial cell surface. Here the micelle dissociates to produce locally high concentrations of monoacylglycerols, lysophosphoglycerols and fatty acids which are absorbed while the bile salts remain in the lumen. The digested lipids are taken up into the absorptive cells by simple transfer from the favourable micellar environment into an apparently unfavourable aqueous one. Clinical implication The importance of bile salts is emphasized by the diminished fat absorption and the steatorrhoea which results from an abnormally low concentration of bile salts in the lumen of the small intestine. There are a number of causes of this low luminal bile salt concentration, the most obvious is biliary obstruction in which the bile duct is blocked, but it can also occur when the liver is diseased, thus causing decreased bile production. Consequently, patients with reduced bile salt concentration are maintained on a low-fat diet. A number of other non-specifiable lipids of importance for example, vitamins A, D, E and Kare also absorbed from mixed bile salt micelles. Consequently, patients suffering from inadequate concentrations of bile salts in the intestine are prone to deficiencies of these vitamins. In such patients, these vitamins can be supplemented for by being administered by injection. Figure 2: Diagrammatic representation of triacylglycerol digestion and absorption (not to scale). 4 After absorption into the intestinal epithelial cells fatty acids are re-esterified to form triacylglycerols. Subsequently, in the small intestine, triacylglycerol, phospholipids, cholesterol and a specific protein called apolipoprotein combine to form spherical chylomicrons with a diameter > 75nm. Chylomicrons contain approximately 85% triacylglycerol, 8% phospholipid, 2% cholesterol, 3% cholesterol ester and 2% protein. They arise solely in the intestine and contain triacylglycerol of dietary origin only. The chylomicrons are released into the blood stream and are subsequently taken up by the liver and by adipose tissue. The association of lipids with proteins not only solubilizes lipids but also aids in their transport into cells. Triacylglycerols are transported to tissues either in chylomicrons or in VLDL. At the cell surface the triacylglycerols are cleaved by lipoprotein lipase to give glycerol and free fatty acids. After absorption into the cell, the glycerol and fatty acids derived from lipoprotein lipase action can be either catabolized to generate energy or, in adipose cells, used to resynthesize triacylglycerols Figure 3: Diagrammatic representation of chylomicron synthesis in an intestinal absorptive cell. Not to scale 5  2) MOBILISATION OF FAT STORED IN ADIPOCYTES The mobilisation of fatty acids from triglyceride deposits in adipose tissue is deeply influenced by hormones. The consumption of meals rich in starch ensures a high concentration of glucose in the blood and hence a high concentration of the hormone insulin. If the concentration of insulin is greater than the hormones, glucagon, and adrenalin, then glycolysis, glycogenesis and the synthesis of fatty acids and other lipids are stimulated. At the same time, the oxidation of fatty acids (β-oxidation) and gluconeogenesis are inhibited. Subsequently under these conditions the mobilization of fats would be inhibited, rather the excessive glucose would be used 1st as energy source. By contrast, under stress conditions, the concentration of blood glucose and [insulin] drops dramatically, whilst the concentration of glucagon and adrenalin become highly elevated. This type of hormonal scenario occurs in starvation, diabetes, trauma, and toxic conditions. The net result would be that glycolysis and glycogenesis would be inhibited due to lack of substrate glucose. Similarly, lipid (TAG) and fatty acid biosynthesis would be inhibited. Since stress conditions would involve an active new source of energy, fatty acid catabolism and gluconeogenesis would now be promoted. Consequently, when blood glucose is low and insulin is low while glucagon and adrenalin concentrations are high, the mobilisation of fats from adipose tissue is promoted. (Figure 4) Figure 4: Mobilization of free fatty acids from adipose tissue by cyclic AMP- mediated cascade system. 6