Metabolism of dietary lipids

Metabolism of Dietary Lipids Biochemistry II What is digestion? Digestion is the breakdown of large molecules into smaller soluble molecules, which can pass through the wall of the gut into the blood.

Metabolism of Dietary Lipids Biochemistry II >90% of dietary lipids = Triacylglycerol (TAG) The remainder consists of phospholipids, cholesterol, cholesterylester and free fatty acids. Lipases can digest dietary lipids into: free fatty acids (FFAs) 2-monoacylglycerol cholesterol lysophospholipids

Problems facing digestion and transport of lipids Metabolism of Dietary Lipids Biochemistry II Problems facing digestion and transport of lipids The insolubility of lipids in water represents a unique problem for the digestion and transport of dietary lipids: On the one hand, enzymes that act on lipids are soluble proteins. On the other hand, lipids and their degradation products, must be transported through aqueous compartments not only within the cell but also in the blood and tissue spaces.

How can the problem of insolubility of lipids in water be overcome? Metabolism of Dietary Lipids Biochemistry II How can the problem of insolubility of lipids in water be overcome? Emulsification Mechanical mixing due to peristalsis Detergent properties of bile salts

What is peristalsis? Peristalsis is the progressive wave of Metabolism of Dietary Lipids Biochemistry II What is peristalsis? Peristalsis is the progressive wave of contractions and relaxations of a tubular muscular system, by which the contents are forced through the system

Metabolism of Dietary Lipids Biochemistry II Bile acids (bile salts) Bile acids (bile salts) are amphipathic cholesterol derivatives with detergent properties. They are secreted into the gallbladder after being formed in liver, and enter the intestine via the bile duct, where they contribute to the digestion of fats and fat-soluble vitamins.

Metabolism of Dietary Lipids Biochemistry II Bile acids (bile salts) Bile acids emulsify lipid globules into smaller micelles, leading to an increase in the surface area accessible to digestive enzymes. They assist in solubilizing lipid breakdown products and preventing them from coalescing.

Bile acids (bile salts) / Emulsification Metabolism of Dietary Lipids Biochemistry II Bile acids (bile salts) / Emulsification

Bile acids (bile salts) Metabolism of Dietary Lipids Biochemistry II Bile acids (bile salts) Secretion of bile salts and cholesterol into the bile by liver is the only mechanism of cholesterol excretion. Most cholesterol and bile acids are reabsorbed in the small intestine and returned to the liver via the portal vein and may be re-secreted. This process is referred to as the enterohepatic cycle. Examples for Substances that interrupt the enterohepatic cycle are : Synthetic resins (Cholestyramine) , as well as soluble fiber (fruit pectin), that bind bile acids and/or cholesterol, prevent absorption/re-absorption. The drug ezetimibe acts on cells lining the lumen of the small intestine and inhibit absorption of cholesterol.

Processing of dietary lipids in the small intestine / TAG Metabolism of Dietary Lipids Biochemistry II Processing of dietary lipids in the small intestine / TAG Pancreatic lipase is an esterase, which preferentially removes the fatty acids at carbons 1 and 3 The primary products are therefore 2-MAGs and FAs. The Enzyme is abundant in a high concentration and is highly efficient  malabsorption observed only in case of severe pancreatic deficiency(e.g. cystic fibrosis)

Processing of dietary lipids in the small intestine / TAG Metabolism of Dietary Lipids Biochemistry II Processing of dietary lipids in the small intestine / TAG Colipase anchors the lipase at the interface of micelles Colipase is secreted by the pancreas as a procolipase, which is activated in the intestine by trypsin. Orlistat, inhibits gastric and pancreatic lipases and decreases thereby fat absorption, resulting in loss of weight.

Metabolism of Dietary Lipids Biochemistry II Mechanism of interfacial activation of triacylglycerol lipase in complex with colipase

Metabolism of Dietary Lipids Biochemistry II Processing of dietary lipids in the small intestine / Cholesteryl ester

Processing of dietary lipids in the small intestine / Phospholipids Metabolism of Dietary Lipids Biochemistry II Processing of dietary lipids in the small intestine / Phospholipids PLA2 Phospholipase A2 (PLA2) is a proenzyme, which needs first to be activated by trypsin. PLA2 removes one fatty acid from carbon 2 of phospholipid, leaving a lysophospholipid, which is a detergent. Lysophospholipase removes the remaining fatty acid at C1, leaving a glycerylphosphoryl base, that might be excreted in the feces, further degraded, or absorbed.

Substrate binding to phospholipase A2 A hypothetical model Metabolism of Dietary Lipids Biochemistry II Substrate binding to phospholipase A2 A hypothetical model No conformational change upon interfacial binding

Control of lipid digestion Metabolism of Dietary Lipids Biochemistry II Control of lipid digestion Low pH of the chyme entering the intestine Presence of lipids and digested proteins Secretion of cholecystokinin (peptide hormone) by the Secretion of secretin (small peptide hormone mucosa of the lower produced by intestinal cells) duodenum and jejunum Contraction of gallblader  release of bile Release of the digestive enzymes of the pancreas Decrease of gastric motility Cause liver and pancreas to release a solution containing bicarbonate  optimal pH for digestive pancreatic enzymes

Dietary Lipids Are Transported in Chylomicrons In the intestinal mucosal cells, the TAG are re-synthesized from FAs and monoacylglycerols. Then packaged into chylomicrons.

Intestinal lumen Intestinal mucosa Dietary TGs Bile salt Other lipids & proteins micelles H2O Pancreatic Lipase Chylomicrons Lymph system FAs TGs Monoglyceroles Intestinal lumen Intestinal mucosa Monoglyceroles FAs lipoprotein lipases Storage in adipose tissue TGs b-oxidation in muscle

Metabolism of Dietary Lipids Biochemistry II The Brush border membrane of the enterocytes = Site of absorption for degraded lipids in mixed micelles. The membrane has an unstirred water layer. Due to the hydrophilic surface of the micelles  easier transport of lipids through the unstirred water layer Aassistance of mixed micelles is not required for absorption Fas (C< 12).

Intestinal fatty acid–binding protein (I-FABP) Metabolism of Dietary Lipids Biochemistry II Intestinal fatty acid–binding protein (I-FABP) The Poorly soluble FAs are sequestered from the cytosol of enterocytes by being bound with intestinal fatty acid binding protein (I-FABP) . This process protects cells from their detergent effect.

Re-synthesis of triacylglycerol and cholesteryl esters Metabolism of Dietary Lipids Biochemistry II Re-synthesis of triacylglycerol and cholesteryl esters Lipids absorbed by the enterocytes migrate to the ER (place where biosynthesis of complex lipids occurs). FAs are first activated by means of fatty acyl CoA synthetase (Thiokinase) 2-MAGs are converted to TAGs by the enzyme complex, TAG synthase; 2 enzyme activities: Acyl CoA:monoacylglycerol acyltranferase Acyl CoA:diacylglycerol acyltranferase

Re-synthesis of triacylglycerol and cholesteryl esters Metabolism of Dietary Lipids Biochemistry II Re-synthesis of triacylglycerol and cholesteryl esters Short and medium-chain fatty cids are not converted to their CoA derivatives. They are transported into the liver using albumin. Chol is esterified to a fatty acid by means of acylCoA : cholesterol-acyltransferase.

Secretion of lipids from enterocytes Biochemistry II Metabolism of Dietary Lipids Secretion of lipids from enterocytes The newly synthesized TAGs and cholesterylesters are very hydrophobic, and aggregate in an aqueous environment. Packing these lipids into a lipid particle surrounded by a thin lipid layer of Pl and Chol and a single protein molecule  chylomicron  Solubility Chylomicrons are released by exocytosis from enterocytes into the lymphatic system and reach thereafter the blood circulation. Coalescence Stability

Use of dietary lipids by the tissues Biochemistry II Metabolism of Dietary Lipids Use of dietary lipids by the tissues Chylomicrons TAGs are broken down in free FAs and glycerol by lipoprotein lipase primarily in the capillaries of skeletal muscle and adipose tissues FAs may directly enter adjacent cells or adipocytes or be transported in the blood in association with serum albumin until taken up by other cells.

Use of dietary lipids by the tissues Biochemistry II Metabolism of Dietary Lipids Use of dietary lipids by the tissues Most cells can oxidize FAs to produce energy. Adipocytes can also re-esterify free FAs to produce TAGs. Chylomicron remnants bind to receptors on the liver and are then endocytosed. Glycerol can be converted into glycerol 3-phosphate, which can enter either glycolysis or gluconeogenesis

Glycerol formed by lipolysis is absorbed by the liver where it enters glycolysis or gluconeogenesis. phosphatase

Noncarbohydrate precursors of glucose Triglycerols glycerol Fatty acids Dietary & muscle proteins Amino acids

Metabolism of Dietary Lipids Biochemistry II Processing of dietary lipid in the stomach Lingual lipase and gastric lipase (secreted by the gastric mucosa) degrade TAGs (C<12). These lipases are of importance for neonates and for patients suffering from cystic fibrosis.

Lipid malabsorption Lipid malabsorption, resulting in increased lipid (including the fats soluble vitamins and essential fatty acids) in the feces (that is, steatorrhea), can lipid be caused by disturbances in absorption digestion and/or Such disturbances can resulted from several conditions, including CF (causing poor digestion) and shortened bowel (causing decreased absorption).