Lipid Metabolism in Tissues Lipid metabolism occurs in the liver We talked about de novo synthesis of FAs In order for us to have TG formation in the liver we need to have Glycerol Kinase or we can have Glycerol 3 Phosphate being formed from the DHAP which is an intermediate in glycolysis Remember that when we compare liver to adipose tissue adipose tissue has no Glycerol Kinase so the only way to form Glycerol 3 Phosphate in the adipose tissue is from DHAP So if we have Glycerol Kinase it means that we are adding a phosphate to Glycerol and DHAP with Glycerol 3 Phosphate Dehydrogenase enzyme We also have the ketone body synthesis in the liver after the buildup of Acetyl CoA That occurs due to oxidation working hard because the accumulation of Acetyl CoA doesn t have enough OAA to bind with and continue TCA Acetyl CoA is then used to synthesize ketone bodies in the liver Those ketone bodies are going to go to the blood stream and organs where they are used as energy In order for them to be used as energy they need to be broken down into Acetyl CoA which then enters the TCA cycle Cholesterol VLDL and HDL synthesis are all in the liver Adipose Tissue Main function is for storage of fat in the form of TG Diets that are high in energy high caloric density and carbohydrates will promote fat synthesis Why Because Insulin is secreted in response to high Glucose in both Okay so you had a big meal so Glucose increases Insulin increases and Glucose starts being up taken by other tissues adipose and muscle require GLUT 4 brain and kidney require GLUT 1 4 and liver require GLUT 2 After being up taken by tissues Glucose is phosphorylated and undergoes glycolysis After all the Glucose that we needed was oxidized the excess Glucose will be used to synthesis Glycogen muscle and liver You still have Glucose left This will be up taken by adipose tissue which will synthesize TG and be stored right there As we already talked about we don t have Glycerol Kinase in the adipose tissue Glycerol 3 Phosphate must then be converted into DHAP which is an intermediate in Glycolysis Here glucose is up taken through GLUT 4 and we have Glycolysis going on with the formation of DHAP DHAP is converted to Glycerol 3 Phosphate by Glycerol 3 Phosphate Dehydrogenase Once you add 3 fatty acids to this Glycerol backbone you are synthesizing you TG or esterifying the fat into TG Adipose Tissue An enzyme that is going to be responsible for acting in lipolysis will be Hormone Sensitive Lipase HSL Lipolysis is the breakdown of TG into Glycerol and fatty acids This enzyme is similar to lipoprotein lipase LPL They both break down TG into Glycerol and fatty acids So HSL is going to be regulated covalently When would lipolysis increase The fasting state or prolonged exercise Glucagon is secreted in these situations Glucagon activates HSL by adding a Phosphate to the enzyme This phosphorylation happens through the action of cAMP Besides Glucagon there are other hormones that lead to the phosphorylation of HSL So independent of the cAMP cascade hormones can activate HSL but we won t talk about that Pretty much we know Catecholamines Epinephrine Norepinephrine and Glucagon are all going to go through the cAMP cascade Then you have your ACTH and Growth Hormone GH which will also increase the activity of HSL This enzyme is active with a phosphate so we know that the presence of Insulin inactivates this enzyme because Insulin stimulates DEPHOSPHORYLATION of an enzyme or prevents phosphorylation What 2 things would Insulin act upon Insulin stimulates Phosphodiesterase which breaks down cAMP into 5 AMP This prevents further phosphorylation of enzymes The other thing is Phosphatase which cleaves the phosphate from the enzymes Insulin is stimulating those 2 Other things such as Methyl Xanthines caffeine and Theophyllines tea have been shown to increase the rate of lipolysis Why They inhibit Phosphodiesterase which prevents the phosphorylation Caffeine and tea will both inhibit phosphodiesterase so if you don t have phosphodiesterase active then you are not preventing the phosphorylation of enzymes because cAMP is still activated and will activate HSL by phosphorylating later Here is lipolysis in adipose tissue the opposite of TG esterification TG in adipose is being broken down by HSL into fatty acids and Glycerol They then go into the blood stream From there FA Glycerol Albumin binding Liver Liver Kidney and intestine oxidation Acetyl CoA Krebs Co Enzymes Oxidized Co Enzymes Phosphorylation of Energy NADP Synthesis of TG Gluconeogenesis Gluconeogenesis In the muscle we have those fatty acids being used as energy we have ketone bodies that are taken up by the muscle for energy and we also have Carnitine which helps get FAs into mitochondria for oxidation Pathway Huge short answer and if you draw it out you must be able to explain especially regulating enzymes Rafaela Feresin This is actually an interaction among a lot of the pathways So we are in our fed state Our increased Glucose levels leads to an increase in secretion of Insulin So how is the Glucose up taken into the tissue Insulin stimulates translocation of GLUT 4 from cytosol to membrane Now Glucose is up taken and then phosphorylated Now it can go in two pathways It can go into Glycolysis with the product of Pyruvate Pyruvate Dehydrogenase then converts it to Acetyl CoA Another product of Glycolysis that we know is important is DHAP Through the action of Glycerol 3 Phosphate Dehydrogenase we can form Glycerol 3 Phosphate Another pathway that will be activated is the HMP Shunt Glucose 6 Phosphate enters HMP Shunt and produces NADPH which is critical for the synthesis of fatty acids Here we have Glucose 6 Phosphate Dehydrogenase which is induced by Insulin We also know PDH is induced by Insulin and is covalently regulated so it is active without the Phosphate Hexokinase is another important enzyme in Glycolysis but it is not regulated by Insulin PFKI will also be induced by Insulin Now we have HADPH Acetyl CoA and Glycerol 3 Phosphate What do we need for TG formation We need to synthesize fatty acid so we can add it to the Glycerol backbone NADPH and Acetyl CoA are being used to synthesize a fatty acid which is Acyl That fatty acid needs to be activated by the addition of a CoA Once you have your Acyl CoA and Glycerol 3 Phosphate you can esterify your fatty acid That is what is happening at higher rates such as fed state lower lipolysis rate At the same time we have lipolysis
View Full Document
Unlocking...