Learning objectives • To understand • How fatty acids are activated and transported into mitochondria for oxidation. • Oxidation of fatty acids. • Role of lipoproteins in cholesterol metabolism.
Introduction • Reserves of stored triglycerides are mobilized as needed for energy production. • Fat mobilization is stimulated by epinephrine. The triglycerides are hydrolyzed to fatty acids and glycerol and enter the blood stream. • Glycerol is converted to glycerol- 3 phosphate and then to dihydroxyacetone phospahte, which enters glycolysis for energy production. • Free fatty acids are converted to fatty acyl CoA molecules, which are broken down to acetyl CoA by beta oxidation. The acetyl CoA may be used for energy production by way of the citric acid cycle and the electron transport chain.
Fatty acid oxidation Fatty acids are degraded to acetyl CoA • Fatty acids enter tissue cells in need of energy. Fatty acids must pass through the mitochondrial membrane to be oxidized and to produce energy. The passage cannot occur until the fatty acid is converted to its thioester with CoA. The product of this reaction is fatty acyl CoA. The reaction is: Fatty acid + HS – CoA+ ATP Fatty acyl CoA + AMP + Pi This is known as activation of fatty acid. Fatty acids must be activated before they are degraded to produce energy. Fatty acids are activated in the cytosol, but oxidation occurs in the mitochondria.
Beta oxidation • The formation of fatty acyl CoA molecule prepares fatty acids for entry into the mitochondria. Carnitine helps fatty acly CoA to enter mitochondria. There they are degraded in the catabolic process called beta oxidation. During beta oxidation, the third (or beta) carbon of the saturated fatty acid chain of the fatty acyl CoA is oxidized to a ketone. • Beta oxidation is a spiral pathway. Each round consists of four enzyme-catalyzed steps that yield one molecule of acetyl CoA and an acyl CoA shortened by two carbons, which becomes the starting substrate for the next round. Seven rounds of beta oxidation degrade a C16 fatty acid to eight molecules of acetyl CoA. Complete oxidation of one molecule of palmitic acid to carbon dioxide and water yields 129 molecules of ATP. One round of beta oxidation yields 17 ATP. Beta Oxidation is regulated by availability of free CoA, by the ratios of NAD/NADH and Q2/QH.
Cholesterol synthesis • Synthesis of cholesterol takes place in cytosol. • The carbon skeleton of cholesterol is formed from acetyl CoA. The pathway of cholesterol biosynthesis has over 30 steps. • The rate determining step of cholesterol synthesis and the major control point is the conversion of HMG-COA to mevolonic acid. • Some intermediate steps of cholesterol synthesis are mevolonic acid— squalene— zymosterol—cholesterol.
The fate of cholesterol • It can be incorporated into a cell membrane. • It may be acylated to form cholesteryl ester for storage. • It is precursor of steroid hormone (estrogen, testosterone) • It is a precursor of bile acids.
Lipoprotein function Chylomicrons, which are mostly lipid, transport dietary lipids to the liver and other tissues. Liver produces triacylglycerol-rich very- low- density lipoproteins (VLDL). As they circulate in the tissues, VLDL give up their triacylglycerol and become cholesterol-rich low- density lipoproteins (LDL), which are taken up by tissues. High Density Lipoproteins transport cholesterol from the tissues back to liver.
LDL Cell can synthesize cholesterol as well as obtain it from circulating LDL. When LDL dock with LDL receptor on the cell surface, the lipoprotein-receptor complex undergoes endocytosis. Inside the cells, the lipoprotein is degraded and cholesterol enters the cytosol. Excess accumulation of cholesterol leads to atherosclerosis.
HDL HDL are essential for removing excess cholesterol from cells. A transporter or flippase moves cholesterol from the cytosolic leaflet to the extracellular leaflet, from which it can diffuse into the HDL. Defects in the gene of the transporter cause Tangier disease, characterized by accumulations of cholesterol in tissues and a high risk of heart attack.