Fat & Protein Metabolism

Fat & Protein Metabolism Introduction to Energy Storage: Our body has evolved a mechanism to store food in order to not be reliant on immediately getting food when we need it A couple different storage types: 1. Glycogen which is stored in the liver (and even some in the muscle) → In a 70 kg male, there is about 480 g of glycogen (4 kcal/g) 2. Proteins are long chains of amino acids and primarily found in the muscles → In a 70 kg male, there is about 6,000 g of protein (4 kcal/g) 3. Fats stored in adipose tissue → In a 70 kg male, there is about 12,000 g of fat (9 kcal/g) You can calculate how long someone can go on each storage of fuel by assuming a man need 2,000 kcal/day Fats are in the molecular form known as triacylglycerides (which is a very energy rich molecule) These fats can vary, some are longer than other while other have saturated/unsaturated carbons The glyceride comes from the backbone of the molecule (the three CHO parts) These molecules often don’t react with a lot of other things since they are insoluble in water Also, fats don’t have much of a functional role in the body, their only use is really for energy Glycogen/protein weighs much more than fat, so it makes more sense to store energy in fat Digestion, Mobilization, & Transport of Fats: Lipases are found in epithelial cells that line the intestines which break down the fats that go throughout the small intestine (cleaves the glyceride backbone from the rest of the fat by adding water) → Leads to the formation of fatty acids (FAs) which are small enough to go into the cell Fats form fatty droplets since they are so hydrophobic Bile is essentially a detergent for our bodies in order to better dissolves/solubilize fats, which increases the surface area for the lipases to work Once the FAs are in the cell we need to get them ready for transport by: 1. Converting them back to Triacylglycerides 2. Package the TAGs into lipoproteins (placing it in the core of a protein molecule known as a chylomicron) 3. Capillaries have openings that are way too small for allowing fat/proteins through so they need to use lacteals (which are the lymphatic vessels of the small intestine which absorb digested fats) and gets into the blood through drainage into the Left/Right Thoracic Ducts (which are veins that go into the circulatory system) Lipoprotein lipases are enzymes found in the capillaries that will break down the TAGs found in the chylomicrons into fatty acids once again The enzyme is also activated by insulin The brain cannot take up fat because fatty acids cannot cross the BBB as well as erythrocytes because they do not contain mitochondria Muscle can take up these free fatty acids because they have a shit ton of mitochondria Adipose tissue are cells with small nuclei and a lot of room to store lots of fat (converts the FAs bag into TAGs for storage as big fatty droplets) These cells have hormone receptors that can detect hormones circulating the body (such as insulin vs glucagon, where an increase in glucagon will signal release of fatty acids into the bloodstream) The fatty acids travel along with Albumin which can now be taken up by different cells throughout the body Any remaining chylomicron lipoproteins leftover, are now known as Chylomicron remnants and get transported to the liver Carbohydrates and other molecules small enough to enter directly into the capillaries, go into a vein that go straight to the liver as well In the liver, glucose can be converted into FAs and any other remaining FAs from the meal which then go into Very Low Density Lipoproteins (VLDLs), which are very similar to that of chylomicrons) The process of gluconeogenesis requires ATP, and therefore uses the ATP made from fats in order to fuel gluconeogenesis Fatty Acid Synthesis - Part 1: We can get fatty acids from the diet, adipose tissue, or from the liver (glucose not being used for glycogen synthesis or breakdown is converted into fatty acids, then TAGs, and packaged into VLDLs) Fatty acid synthesis typically refers to the formation of fatty acids from glucose in the liver (glucose is broken down like normal until it is converted into acetyl-CoA, however, the enzymes needed to convert acetyl-CoA into fatty acids are located within the cytoplasm There is however a way to get citrate back into the cytoplasm, where it is broken down into acetyl-CoA and oxaloacetate (which is no longer needed and therefore converted into pyruvate so that it can be shuttled back into the mitochondria → lose a CO2 molecule in that process since you are going from a four carbon molecule to a three carbon molecule, and since OAA is oxidized, NADP+ is reduced to NADPH) Multiple Acetyl-CoA, ATP, and NADPH are used/needed in order to form fatty acids Remember, NADPH is mainly generated by the pentose phosphate pathway (PPP) but is also formed here (they are important for providing reducing power needed for anabolic reactions) → used to reduce the carbonyl groups on acetyl-CoA Fatty Acid Synthesis - Part 2: Anabolic reactions typically involve the polymerization of a monomer (the issue with this is that they have ΔG > 0 and are therefore not spontaneous) In order to push the direction forward, we couple it with ATP hydrolysis which has a ΔG << 0, making the overall reaction less than 0 The product of this is a fatty acid known as Palmitic Acid (16-carbon molecule) Overall reaction: 8Acetyl-CoA + 7ATP + 14NADPH → Palmitic Acid + 7ADP +7Pi + 14NADP+ + 6H2O + 8CoA Once in the cytoplasm with Acetyl-CoA: 1. Convert acetyl-CoA to a higher energy product known as Malonyl-CoA (uses ATP coupling because of higher energy state and CO2) a. Enzyme known as Acetyl-CoA Carboxylase is used and is regulated because this is the rate limiting step (slowest kinetically) i.Regulated allosterically: activated by citrate and inhibited by Fatty acids ii.Regulated hormonally: activated by insulin and inhibited by glucagon 2. Malonyl-CoA loses H2O, CO2 and uses 2NADPH in order to reduce 2 carbonyl bonds, and does this until it reaches a 16 carbon Palmitic Acid (completely saturated fatty acid) a. Enzyme known as Fatty Acid Synthase is used in the second step to generate the 16 carbon fatty acid Overview of Fatty Acid Oxidation: 95% of the energy extracted from a TAG comes from the fatty acid chains and the remaining 5% comes from the glycerol backbone which it can enter glycolysis Remember, just how glucose was oxidized, these fatty acid chains must also be oxidized in order to reduce electron carrier molecules like NADH and FADH2 (do this by breaking up palmitic acid into subunits of acetyl-CoA) Also, acetyl-CoA can then enter the Krebs cycle which can then contribute to even more energy (produced 8 acetyl-CoA molecules) 27 ATP are produced through the oxidation of Palmitic Acid and another 80 ATP from the 8 acetyl-CoA molecules that enter the Krebs Cycle (already takes into account the ETC) Fatty Acid Oxidation - Parts I & II: 3 Main steps to Fatty Acid Oxidation: 1. Activate: this is done by reacting the FA with coenzyme A (CoA-SH) forming Acyl-CoA (acyl meaning its a long fatty acid chain and acetyl means it’s just a methyl group) and is coupled with the reaction of ATP → AMP. Next, carnitine is attached to the Acyl molecule (CoA leaves) a. Enzyme used for these reactions respectively are located on the outer mitochondrial membrane and is called Acyl Synthetase and Carnitine Acyl Transferase I (rate limiting step and is therefore malonyl-CoA allosterically inhibits CATI since we’re synthesizing fatty acids and we don’t need them to be broken down) 2. Transport: the acyl-Carnitine molecule can now move across the outer membrane through one of the pores on the outer mitochondrial membrane. The protein transporter known as Acyl-Carnitine Translocase allows the passage of acyl carnitine into the mitochondrial matrix. a. Now inside the matrix, Carnitine Acyl Transferase II takes the carnitine molecule and replaces with with a CoA group, reforming Acyl-CoA (carnitine can return to the cytoplasm through the acyl carnitine transferase) 3. Oxidation: basically you form Acetyl-CoA and generate electron carriers NADH and FADH2 (water and CoA-SH groups are used in order to keep the cycles going) “ꞵ-Oxidation” refers to this process because the beta carbon is the one becoming the new carbonyl How does the body adapt to starvation?: In order to survive, we must maintain glucose levels in our blood Glycogen only lasts for a day and then begins relying on gluconeogenesis from fatty acids (which can’t be directly used in gluconeogenesis) and amino acids (these can be though) Amino acids can be converted into krebs cycle intermediates You cannot go backwards from acetyl-CoA to Pyruvate because the ΔG << 0, greatly favoring the forwards reaction (making fatty acids unable to be used in the gluconeogenesis pathway) Also, even though acetyl-CoA enters the Krebs Cycle, the 2 C atoms from acetyl-CoA leave as 2CO2 molecules and is therefore a permanent product In order to save protein during periods of starvation, we switch to ketone bodies for energy sources (can cross the BBB) In times of fasting, glucagon concentration increases while insulin concentration decreases Increase acetyl-CoA concentration in the body allows it to be shunted into the production of ketones within the liver and ships it to the body, allowing gluconeogenesis some breathing room Protein degradation mainly happens in first 1-3 days, but after that ketosis kicks in Overview of Amino Acid Metabolism: Amino acid metabolism only contributes to about 10-15% of our cell’s total energy production Essential amino acids are the amino acids that our body cannot synthesize (there are 10: phenylalanine, valine, tryptophan, threonine, isoleucine, methionine, histidine, arginine (MAYBE NOT??), leucine, and lysine → “PVT Tim Hall”) Non-essential amino acids are amino acids that our body can synthesize (all the others) Carbon backbone can be converted into precursor molecules of either glucogenic or ketogenic pathways (one is glucose pathway and the other is the fatty acid pathway) 2 amino acids that are exclusively ketogenic (lysine and leucine) Now, typically with amino acid conversion, you want to take off the amino group from the molecule in a step known as transamination (where the amine group on the aa is transferred to another molecule for excretion by the body) and forms an ɑ-Keto acid ɑ-ketoglutarate (an intermediate in the Krebs cycle) accepts this amine group and is converted into glutamate (in the liver it donates the NH3 and it will enter the urea cycle to rid it from the body because it is toxic at high levels) Extra Notes: The longer the fatty acid, the more energy, and the more saturated, the more reduced and therefore the more energy it has