Fat catabolism: generation of energy by fatty acid oxidation

1. Fat catabolism: generation of energy by fatty acid oxidation Fat (triacylglycerol) and Fatty Acids: 90% of dietary lipids are tryacylglycerol, a hydrophobic, neutral molecule made from reaction of OH group of glycerol and COO- group of fatty acids. Fatty acids are made up of a long hydrophobic hydrocarbon chain (highly reduced) and a carboxylic acid polar group. Different kinds of fatty acids play very important structural (as major component of membrane structures) and functional role. In this part of discussion we will mainly focus of the digestion, transport and catabolism of triglycerides. Although other lipids like cholesterol, sphingolipids are important too but they will not be covered in this course. Sources of Fat available for oxidation: 1. Dietary fat, 2. Excess dietary fat stored in adipose tissue and 3. Excess carbohydrate calories are converted to FAT in liver and transported to adipose tissues. Function: -Stored fat acts as major energy source when there is no carbohydrate available, -it also serves as source for supply of fatty acids required for important cellular function provide insulation and complexion to body

2. Michael Cooper Has cut his calorie intake to nearly half of the daily requirement. He does not have any fat storage, thus he faces the following problems; 1. Looks sick: bad complexion or look 2. He feels terribly cold even at 20 oC: no insulation. 3. Cannot afford to starve even for a few days; no fat store to sustain survival.

4. Different kinds of lipids We will focus on catabolism of storage lipids. Cholesterol plays an important role in transport and metabolism of lipids.

5. Tri-acylglycerols (fat) molecules are highly hydrophobic. After ingestion they are present in the form of oil droplets. In order to get digested and absorbed, they need to be emulsified (partially solubilized. Liver produces bile acids which are collected in gall bladder and released into intestine, where they in emulsification of fat. Bile acids are amphipathic, detergent like molecules capable of binding to hydrophobic as well as hydrophilic molecules.

6. Some important players involved in lipid digestion and transport: Bile Acids:These are amphiphathic (with polar and non-polar structures) detergent like molecules synthesized in liver. They help solubilize or emulsify the triglycerides (fat) in the small intestine. Pancreatic Lipases:These are pancreatic enzymes that catalyze the hydrolysis of fat to release fatty acids and glycerol in intestine. Bile acid and Fatty acid binding proteins:They facilitate absorption of lipids in intestine. Intestinal Fatty acid binding proteins (I-FABP):these proteins are present inside the intestinal cells, they bind to fatty acids and protect cells from the detergent like behavior of fatty acids. Chylomicrons:These are lipoprotein granules containing specific lipoproteins, dietary cholesterol, phospholipids and triacylglycerol. These transport granules transport cholesterol and lipids from intestine to adipose tissues and liver via blood. Lipoprotein lipase:These enzymes are present in the capillaries of the peripheral tissues. They digest triglycerides into Fatty acid and glycerol.

9. Lipid Transport: Chylomicrons transport cholesterol and lipids from intestine to adipose tissues and liver via blood. Very low density lipoproteins (VLDL): are synthesized in liver and transport endogenous triacylglycerol and cholesterol from liver to adipose and muscle tissue. Capilary lipoprotein lipases degrade VLDL and fatty acid and glycerol are delivered to adipocytes or muscle. After giving up their triacylglycerols, the VLDL remnants appear in the blood as Intermediate density lipoproteins (IDL) and then as low density lipoproteins (LDL). IDL and LDLs are taken back by liver by specific receptor mediated endocytosis. High density lipoproteins (HDL) are assembled from the degradation products of other lipoproteins. HDLs mop up excess cholesterol from other tissues and deliver it to liver.

11. Utilization of stored fat • Low blood glucose and energy need trigger the secretion of epinephrine and glucagon hormones • Activation of adnylate cyclase • Production of cAMP • Activation of cAMP-dependent protein kinase • Phosphorylation and activation of triacylglycerol lipase • Release of fatty acids in blood and binding of fatty acids to serum albumin • Transport of FA through serum albumin to the muscle tissues • B-oxidation of FA to produce acetyl CoA.

12. Catabolism of glycerol after lipase reaction: After the triacylglycerol (fat) is digested by lipase, it releases fatty acids, and glycerol. Glycerol can be converted to glycerol 3 phosphate and then to dihydroxy acetone phosphate (DHAP). DHAP is converted to Glyceraldehyde 3 P by triose phosphate isomerase (reaction # 5) which enters the GAPDH reaction (reaction # 6)of glycolysis directly.