Dr. Diala Abu-Hassan, DDS, PhD Lipid Metabolism Dr. Diala Abu-Hassan, DDS, PhD Dr.abuhassand@gmail.com Nursing All images were taken from McMurry et al except where noted Dr. Diala Abu-Hassan00

Digestion of triacylglycerols (TAGs) TAGs are not water-soluble but they must enter an aqueous environment TAGs are packaged in various kinds of lipoproteins Energy can drive chemical reactions that are not favorable at body temperatures. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

Lipoproteins In the duodenum, pancreatic lipases and bile acids are released to emulsify the TAGs by forming micelles Dr. Diala Abu-Hassan

Bile salts Bile acids (derived from cholesterol) and cholesterol, which are steroids, and phospholipids are released to emulsify the TAGs by forming micelles Dr. Diala Abu-Hassan

TAGs Digestion Dr. Diala Abu-Hassan

Pathways of lipids through the villi Lipoproteins (chylomicrons ) – lacteal- thoracic duct- blood Dr. Diala Abu-Hassan

Sources of lipids from the digestive tract as food is broken down (2) from adipose tissue, where excess lipids have been stored (3) from the liver, where lipids are synthesized. Dr. Diala Abu-Hassan

Lipid transport 10 FA by 1 albumin Dr. Diala Abu-Hassan

Types of lipoproteins 1. Very-low-density lipoproteins (VLDLs) carry TAGs from the liver (where they are synthesized) to peripheral tissues for storage or energy generation. 2. Intermediate-density lipoproteins (IDLs) carry remnants of the VLDLs from peripheral tissues back to the liver for use in synthesis. 3. Low-density lipoproteins (LDLs) transport cholesterol from the liver to peripheral tissues, where it is used in cell membranes, for steroid synthesis, or for formation of arterial plaque 4. High-density lipoproteins (HDLs) transport cholesterol from dead or dying cells back to the liver, where it is converted to bile acids. Dr. Diala Abu-Hassan

Metabolism of triacylglycerols Dr. Diala Abu-Hassan

Dietary Triacylglycerols TAG hydrolysis occurs when chylomicrons in the bloodstream encounter lipoprotein lipase anchored in capillary walls. Fatty acids (FAs) are then: (1) When energy is in good supply, they are converted back to TAGs for storage in adipose tissue (2) When cells need energy, the FA carbon atoms are activated by conversion to fatty acyl-SCoA and then oxidized as acetyl-SCoA Acetyl-SCoA is the starting material for the biosynthesis of fatty acids (lipogenesis) in the liver and the synthesis of cholesterol Acetyl-SCoA enters the ketogenesis pathway for production of ketone bodies Dr. Diala Abu-Hassan

Triacylglycerols from Adipocytes When stored TAGs are needed as an energy source, lipases within fat cells are activated by hormones (insulin and glucagon) The stored TAGs are hydrolyzed to FAs and glycerol- blood (in association with albumins to cells (primarily muscle and liver cells))- acetyl-SCoA - energy generation. Dr. Diala Abu-Hassan

Glycerol from Triacylglycerols Glycerol- blood to kidney and liver - converted glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) DHAP, a reactant in the synthesis of triacylglycerols, enters the glycolysis pathway Dr. Diala Abu-Hassan

Storage and Mobilization of Triacylglycerols TAGs are the primary energy storage form. TAGs are stored in the adipose tissue After a meal, insulin activates the synthesis of TAGs for storage. After a meal, blood glucose levels increase rapidly, insulin levels rise, and glucagon levels drop. Glucose enters cells, and the rate of glycolysis increases. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

TAG Mobilization When digestion of a meal is finished, blood glucose levels return to normal, insulin levels drop and glucagon levels rise. This activates triacylglycerol lipase to start the hydrolysis of stored TAGs. When glycerol 3-phosphate is in short supply (glycolysis is not producing sufficient energy) the FAs and glycerol produced by TAG hydrolysis are released to the bloodstream for transport to energy-generating cells. Otherwise, the fatty acids and glycerol are cycled back into new TAGs for storage. Dr. Diala Abu-Hassan

Oxidation of Fatty Acids A fatty acid enters the cytosol of a cell that needs energy then, 1. Activation 2. Transport to mitochondria Carnitine, an amino-oxy acid, undergoes a transesterification reaction with the fatty acyl- SCoA, resulting in a fatty acyl carnitine ester that moves across the membrane into the mitochondria by facilitated diffusion. 3. β-Oxidation Pathway Dr. Diala Abu-Hassan

β-Oxidation of Fatty Acids 3. β-Oxidation Pathway: fatty acyl-SCoA is oxidized to acetyl-SCoA and the reduced coenzymes to be used in ATP generation. Spiral pathway (4 steps repeated or each 2 carbon fragment) Dr. Diala Abu-Hassan

Energy from Fatty Acid Oxidation Lauric acid Carbohydrates yield 4 Cal/g, whereas fats and oils yield 9 Cal/g Dr. Diala Abu-Hassan

Ketone Bodies Ketone body formation in liver mitochondria Acetoacetate is somewhat unstable Ketone bodies are water soluble, thus, they do not need protein carriers to travel in the bloodstream Dr. Diala Abu-Hassan

Ketogenesis It is the synthesis of the three ketone bodies from acetyl-SCoA Ketogenesis occurs in four enzyme-catalyzed steps plus the spontaneous decomposition of acetoacetate. The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. (HMG-CoA) Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

3-hydroxybutyrate dehydrogenase Ketogenesis 3-hydroxybutyrate dehydrogenase The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

Ketogenesis In normal person, skeletal muscles derive a small portion of their daily energy needs from acetoacetate, and heart muscles use it in preference to glucose when fatty acids are in short supply. During early stages of starvation, heart and muscle tissues burn more acetoacetate and save glucose for brain tissue In diabetic patients, more ketone bodies are produced than they are utilized (ketosis) Ketosis is indicated by the odor of acetone (a highly volatile ketone) on the patient s breath and the presence of ketone bodies in the urine (ketonuria) and the blood (ketonemia). The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

Biosynthesis of Fatty Acids (lipognesis) Fatty acids are synthesized from acetyl-SCoA Acetyl-SCoA is an end product of carbohydrate and amino acid catabolism Using acetyl-SCoA to make fatty acids allows the body to use the excess energy of carbohydrates and amino acids into storage as TAGs The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

Fatty acid synthesis (lipogenesis) FA synthase complex The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. (Fatty acid synthase is a multienzyme complex that contains all six of the enzymes needed for lipogenesis, with a protein called acyl carrier protein (ACP) anchored in the center of the complex.) Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan

Fatty acid synthesis (lipogenesis) Palmitic acid production (16 carbons) Step 1: Condensation Steps 2-4 Reduction Dehydration 7 times The enzyme for the pathway, also found in mitochondria, has the same name but is specific for the L form of 3-hydroxy-3-methylglutaryl-SCoA. The pathways are separated by the specificity of the enzymes for their respective substrates. Dr. Diala Abu-Hassan Dr. Diala Abu-Hassan