BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 14. LIPID METABOLISM

14.1. Digestion and Transformation of Lipids in the Gastrointestinal Tract

Lipids entering the bodies of animals and humans with food daily are represented mainly by fats of PLANT AND ANIMAL origin (~50-60 g), as well as Phospholipids (~10 g), Cholesterol, and its esters (~0.5 g). The breakdown of dietary lipids is carried out via Hydrolysis involving lipolytic Enzymes of the gastrointestinal tract: triacylglycerol lipase, phospholipases, and cholesteryl esterases.

In the Oral Cavity, lipids do not undergo any transformations due to the absence of lipolytic enzymes in saliva; their Digestion begins in The Stomach, which contains triacylglycerol lipase. However, this enzyme is active only in newborn mammals and infants, in whose stomachs the pH of the medium (5-5.5) corresponds to the pH optimum of this enzyme. In the acidic environment of the adult human stomach, lipase is inactive, and therefore the hydrolytic breakdown of fats and other lipids essentially takes place in the Small Intestine.

The upper section of the small intestine—the duodenum, along with the Pancreas and Liver—serves as the "center" of digestion for all food components, including lipids.

The arrival of chyme and the resulting acidification in the duodenum trigger the secretion of the Hormones secretin and cholecystokinin by the Cells of the small intestinal mucosa. Secretin stimulates the secretion of pancreatic juice with a high concentration of bicarbonates (up to 150 mmol/L in humans) and a low enzyme content. As a result of the neutralization of the acidic environment by bicarbonates, optimal conditions for fat hydrolysis are established:

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In the pancreatic secretion that continues to flow into the duodenum, The ratio of inorganic and organic components changes, with the latter predominating, particularly protein-enzymes. Inactive lipolytic enzymes are activated in the lumen of the duodenum. The activator of triacylglycerol lipase is the protein colipase, which is secreted along with lipase. The necessary conditions for the catalytic activity of lipase, In addition to the presence of colipase and a neutral medium reaction, also include the presence of emulsifiers. Since the lipid hydrolysis reaction can occur only at the interface between the aqueous and lipid phases, the efficiency of catalysis depends on the magnitude of the available interfacial area, i.e., the degree of fat emulsification. The smaller the fat droplets, the more accessible the surface area for hydrolysis. Therefore, milk—a fine emulsion of fat in Water—is an ideal substrate for lipase. Bile acids are the primary natural emulsifiers of fats.

By nature, bile acids are Steroids, derivatives of cholesterol. Out of more than 30 known bile acids, the most important are cholic and chenodeoxycholic acids, along with their derivatives—deoxycholic and lithocholic acids. Bile acids are synthesized in the liver as conjugates with Glycine and taurine (Fig. 14.1). Glycine-conjugated bile acids (glycocholates) are characteristic of mammals. In humans, the content of glycocholates is about 75%, and the proportion of taurocholates is 25%; however, in primates and other animals, conversely, taurocholates predominate.

Bile acid conjugates accumulate in the Gallbladder and, at a concentration of approximately 2 mmol/L within bile along with

phospholipids and cholesterol, form micelles, thereby maintaining cholesterol in a soluble state. If micelle formation is disrupted (due to an increased cholesterol content or a decreased concentration of bile acids or phospholipids), cholesterol can precipitate in the bile ducts and form gallstones. Within bile, bile acid conjugates easily ionize, forming salts predominantly with Na⁺. Due to the amphipathic properties of bile acid salts and their conjugates—dictated by the hydrophilicity of the glycine and taurine residues and the Structure/106.html">Hydrophobicity of the steroid Nucleus—bile acid conjugates and their salts act as effective natural detergents. Phospholipids, monoacylglycerols, and intestinal peristalsis also facilitate the emulsification of dietary fats. Under the action of emulsifiers, the surface tension of fat droplets decreases, causing them to break down into smaller structures known as micelles.

Fig. 14.1. Scheme of glycocholate and taurocholate synthesis

Fat hydrolysis takes place On the surface of these structures through the action of lipase, which rapidly cleaves the ester bonds in triacylglycerol molecules at the α- and γ-positions, releasing Fatty acids and β-monoacylglycerol:

The hydrolysis of dietary lipids in the duodenum occurs under hormonal control, particularly mediated by cholecystokinin, which is released when lipid digestion products appear in the intestine. It stimulates the secretion of BILE AND PANCREATIC enzymes, thereby sustaining the digestive process.

The hydrolysis of phospholipids, occurring simultaneously with fats, is catalyzed by phospholipases, which are also secreted by the pancreas (Fig. 14.2):

Fig. 14.2. Specificity of action of various phospholipases

Following activation by Trypsin, phospholipases sequentially cleave the ester bonds of the lipid molecule: first, phospholipase A2 hydrolyzes the ester bond at carbon-2 of the phospholipid molecule, yielding a lysophospholipid; subsequently, with the participation of phospholipases A₁, C, and D, the fatty acid is cleaved off, releasing Choline, glycerol, and phosphoric acid.

Cholesteryl esters (cholesterol esters) entering the body with food are broken down by pancreatic cholesterol esterase, releasing free cholesterol and fatty acids.

All lipid hydrolysis products in the small intestine, together with bile acids, are absorbed by the cells of the small intestinal mucosa. At the same time, molecules of glycerol, amino alcohols, phosphoric acid, and short-chain fatty acids pass freely—via passive diffusion—into enterocytes, then into the intercellular space, and subsequently enter the liver via the portal vein Blood flow.

Amphiphilic products of lipid breakdown—Higher Fatty Acids, monoacylglycerols, and Fat-soluble Vitamins—together with bile acids and cholesterol, form mixed micelles and are transported in this form into the mucosal cells, where the micelles disintegrate into their constituent parts.

The released bile acids enter the liver via the portal vein blood and are reused in lipid hydrolysis. The efficiency of this bile acid reutilization, known as enterohepatic Circulation, is nearly 90%. Other components of mixed micelles—monoacylglycerols, higher fatty acids, cholesterol, and phospholipids—participate in The formation of lipid-Protein Complexes called chylomicrons. The lipid and protein components of chylomicrons are synthesized on the membranes of The Endoplasmic reticulum in the cells of the small intestinal mucosa: lipids are resynthesized on the membranes of the smooth reticulum, while specific chylomicron Proteins—apoproteins—are synthesized on Ribosomes.

The resynthesis of triacylglycerols is carried out via direct Esterification of β-monoacylglycerols with fatty acid CoA esters. In the Reactions of the so-called monoacylglycerol shunt, Fatty acids are first activated by a synthetase in the presence of CoA-SH and are subsequently transferred by Acyltransferases to β-monoacylglycerol:

Certain phospholipids are resynthesized in the very same manner. Resynthesized lipids and synthesized apoproteins, specifically apoprotein B, form chylomicrons through lipid-lipid and Lipid-Protein Interactions. These are small spherical structures with a diameter of ~1 µm, composed of triacylglycerol molecules (85 %), cholesterol and its esters (up to 6 %), as well as phospholipids (~7 %) and proteins (2 %), which form a hydrophilic shell around the Hydrophobic core.

From the mucosal cells, chylomicrons enter the intercellular space and lacteals (the Lymphatic vessels of the intestinal villi) via exocytosis. Due to the high concentration of chylomicrons during the absorptive period, the normally clear post-absorptive Lymph turns milky-white. Through the Thoracic duct, chylomicrons enter the bloodstream, where The transfer of apoprotein C from high-density Lipoproteins converts nascent (immature) chylomicrons into mature ones. The presence of apoprotein C is essential for the activation of lipoprotein lipase, an enzyme localized on the inner surface of the capillary endothelium in adipose and other Tissues. Upon activation, lipoprotein lipase catalyzes the hydrolysis of chylomicron triacylglycerols, and the hydrolysis products are assimilated by tissues—either utilized for the synthesis of endogenous fats, as in adipose tissue, or degraded to meet energy demands, as in Muscles and other Organs (Fig. 14.3 (after N. V. Bhagavan, 1978)).

Fig. 14.3. Scheme of chylomicron formation and degradation.

The half-life of triacylglycerols in chylomicrons ranges from a few minutes to an hour, after which the so-called remnant chylomicrons are cleared from the bloodstream and metabolized by the liver via specific receptors found exclusively on hepatocyte Plasma Membranes. Thus, native chylomicrons serve as the transport form for exogenous triacylglycerols.

In hereditary deficiency of lipoprotein lipase activity in the circulatory capillaries—hyperchylomicronemia—There is a persistently high level of blood chylomicrons, which sharply increases during the absorptive period, accompanied by subcutaneous fat deposition and Chronic Pancreatitis.