Topic 20: Lipid Metabolism Flashcards
How are fatty acids stored?
Fatty acids are stored as triacylglycerols (triacylglycerides or triglycerides) in adipose tissue. This fuel-rich tissue is located under the skin as subcutaneous fat and surrounds the internal organs as visceral fat.
How are triglycerides broken down upon enterin our stomachs?
Lipids are prepared for digestion in the stomach. The grinding and mixing that takes place in the stomach converts lipids into an emulsion, a mixture of lipid droplets and water. After the lipids leave the stomach, emulsification is enhanced with the aid of bile salts, amphipathic molecules synthesized from cholesterol in the liver and secreted to the gallbladder in response to cholecystokinin. These molecules insert into the lipid droplets, making the triacylglycerols more readily digested.
Triacylglycerols are then degraded to free fatty acids and monoacylglycerols (MAG) by enzymes secreted in the pancreases called lipases, which attach to the surface of a lipid droplet. Pancreatic lipases are released into the intestine as zymogens that are subsequently activated. The final digestion products, free fatty acids, and monoacylglycerol, are carried in micelles globular structures formed by small lipids in aqueous solutions) to the plasma membrane of intestinal epithelial cells where they will subsequently be absorbed
What do intestinal cells do with the fatty acids/monoacylglycerols?
The fatty acids and monoacylglycerol are transported into the intestinal cells by membrane proteins such as the fatty-acid binding protein (FABP). Once inside the cell, fatty acid-transport proteins ferry them to the cytoplasmic face of the smooth endoplasmic reticulum, where the triacylglycerols are resynthesized from fatty acids and monoacylglycerol.
After being transported to the lumen of the SER, the triacylglycerols associate with specific proteins and a small amount of phospholipid and cholesterol to form lipoprotein transport particles called chylomicrons, stable particles about 200 nm in diameter. These particles are about 98% triacylglycerols with the proteins and phospholipid on the surface. Chylomicrons are vehicles for transporting dietary fats from the intestines to other tissues for energy or storage. They are part of the complex system that regulates lipid metabolism in the body. The chylomicrons are released into the lymph system and then into the blood, bound to albumin. For this reason, after a lipid rich meal, blood appears milky.
These particles bind to membrane-bound lipoprotein lipases, primarily at adipose tissue and muscle, where the triacylglycerols are once again degraded into free fatty acids and monoacylglycerol for transport into the tissue. The triacylglycerols are then resynthesized and stored. In the muscle and other tissues, they can be oxidized to provide energy, as will be discussed soon
What are the three stages of fatty acid processing
Peripheral tissues such as muscle gain access to the lipid energy reserves stored in adipose tissue through three stages of processing.
First, the lipids must be mobilized. In this process of lipolysis, triglycerides are degraded to fatty acids and glycerol, which are released from adipose tissue and transported through blood to the energy-requiring tissue.
Second, at these tissues, the fatty acids must be activated as CoA esters and transported through into mitochondria for degradation
Fatty acids are then broken down in a step-by-step fashion into acetyl coA, which can enter the citric acid cycle.
How are lipids mobilized
Triacylglycerol mobilization and deposition take place on the surface of the droplet. Before fats can be used as fuels, triacylglycerol must be hydrolyzed to yield more accessible fatty acids. This is triggered by hormones epinephrine and glucagon, which trigger 7TM (transmembrane) receptors, which activate adenylate cyclase, a membrane bound enzyme that catalyzes the conversion of ATP to cAMP.
The increased levels of cyclic AMP stimulates protein kinase A, which phosphorylates two key proteins, perilipin, a lipid-droplet associated protein, and hormone-sensitive lipase. The phosphorylation of perilipin has two crucial effects. First, it restructures the fat droplet so that the triglycerides are more accessible to degradation. Second, the phosphorylation of perilipin triggers the release of a coactivator for adipose triglyceride lipase (ATGL).
Once bound to the cofactor, ATGL initiates the mobilization of triacylglycerols by releasing a fatty acid from triacylglycerol, forming diacylglycerol
Diacylglycerol is converted to a free fatty acid and a MAG by the hormone-sensitive lipase, which has been activated by phosphorylation
Finally, a monoacylglycerol lipase completes the mobilization of fatty acids with the production of a free fatty acid and glycerol. Thus, epinephrine and glucagon induce lipolysis
How are fatty acids activated
First, fatty acids must be activated by reacting with coenzyme A to form acyl CoA. This activation reaction takes place on the outer mitochondrial membrane, where it is catalyzed by acyl CoA synthetase
This activation occurs in two steps:
The fatty acid reacts with ATP to form acyl adenylate, and the two other phosphoryl groups of the ATP substrate are released as pyrophosphate
The sulfhydryl group of CoA then attacks the acyl adenylate to form acyl CoA and AMP
How is the acitvated fatty acid brought into the cell
Activated fatty acids can cross the outer mitochondrial membrane through voltage gated ion channels, also called porin channels, but transport across the inner mitochondrial membrane requires that the fatty acids be linked to the alcohol carnitine.
The acyl group is transferred from the sulfur atom of CoA to the hydroxyl group of carnitine to form acyl carnitine. This reaction is catalyzed by carnitine acyltransferase I (also called carnitine palmitoyltransferase I), which is bound to the outer mitochondrial membrane
Acyl carnitine is then shuttled across the inner mitochondrial membrane by a translocase. The acyl group is transferred back to CoA by carnitine acyltransferase II on the matrix side of the membrane. Finally, the translocase returns carnitine to the cytoplasmic side in exchange for an incoming acyl carnitine, allowing the process to continue
Describe how fatty acids are broken down once in the matrix
The goal of fatty acid degradation is to oxidize the fatty acid, two carbons at a time, to acetyl CoA, to gather the released high-energy electrons to power oxidative phosphorylation. A saturated acyl CoA is degraded by a recurring sequence of four reactions: oxidation by FAD, hydration, oxidation by NAD+ and thiolysis by coenzyme A
The fatty acid chain is shortened by two carbon atoms as a result of these reactions, and FADH2, NADH and CoA are generated. Because the oxidation takes place at the β-carbon atom, this series of reactions is called the β-oxidation pathway.
The first reaction in each round of degradation is the oxidation of acyl CoA by an acyl CoA dehydrogenase to give and enoyl CoA with trans double bond between C2 and C3
As in the dehydrogenation of succinate in the citric acid cycle, FAD is the electron acceptor rather than NAD+ because the ∆G for this reaction is insufficient to drive the reduction of NAD+. Electrons picked up by FAD are transferred to the electron transport chain
The next step is the hydration of the double bond between C-2 and C-3 by enoyl CoA hydratase. This is stereospecific, only the L-isomer of 3-hydroxyl CoA is formed.
The hydration of enoyl CA is a prelude to the second oxidation reaction, which converts the hydroxyl group at C-3 into a keto group, generating NADH, being catalyzed by L-3 hydroxyacyl CoA dehydrogenase
The preceding reactions have oxidized the methylene group at C-3 to a keto group. The final step is the cleavage of 3-ketoacyl CoA by the thiol group of a second molecule of coenzyme A, which yields acetyl CoA and an acyl coA shortened by two atoms
This thiolytic cleavage is catalyzed by β-ketothiolase
The shortened acyl CoA then undergoes another cycle of oxidation, starting with the reaction catalyzed by acyl CoA dehydrogenase
