Study Guide Exam 3 LIVER LIPID METABOLISM IN DeNovo fatty acid synthesis DeNovo means FA synthesis from non fat substances Glycerol 3 P04 Formed from Glycerol via Glycerol Kinase DHAP via Glycerol 3 PO4 Kinase Note Glycerol and DHAP are both used to form Glycerol 3 P04 in the LIVER In Adipose tissue however there is no glycerol kinase the enzyme needed to convert glycerol into Glycerol 3 P04 so only DHAP can be used in the Adipose tissue to form Glycerol 3 PO4 Also just because the Adipose Tissue doesn t make Glycerol 3 P04 from Glycerol doesn t mean that Glycerol isn t in the Adipose tissue In fact Glycerol is formed in the Adipose tissue via Glycolysis Once the Glycerol is formed it must be transferred to other tissues that have Glycerol Kinase such as the Liver Ketone Body Synthesis Cholesterol Synthesis VLDL HDL Synthesis ADIPOSE TISSUE LIPID METABOLISM IN Major Function FAT STORAGE LIPOGENESIS Note Diets that promote fat synthesis storage High Carbohydrate High Energy Glucose Insulin favors Fat Storage Again In Adipose Tissue Glycerol 3 PO4 needed for Synthesis of TAGS and Phospholipids MUST BE FORMED FROM DHAP Adipose Tissue lacks Glycerol Kinase which is the enzyme that changes Glycerol into Glycerol 3 PO4 This process is favored by INSULIN LIPOLYSIS Hydrolysis of Triacylglycerol TAGS Lipolysis is catalyzed by the enzyme HORMONE SENSITIVE LIPASE HSL HSL induces lipolysis under the same conditions as oxidation HSL cleaves TAGS into Free Fatty Acids Glycerol in the Adipose Tissue HSL Regulation Primarily Covalent Modification Stimulated By Catecholamines epinephrine norepinephrine Glucagon Adrenocorticotropic Hormone ACTH Growth Hormone GH Methyl Xanthines ex CAFFEINE 1 Inhibited By Insulin Note Insulin inhibits HSL by promoting a dephosphorylation by the enzyme protein lipase and stimulating phosphodiesterase Protein Lipase cleaves a PO4 from HSL inactivating it Phosphodiesterase is responsible for the breakdown of cAMP which will inhibit HSL by decreasing phosphorylation Note Methyl Xanthines inhibit phosphodiesterase from breaking down cAMP which in turn will prolong LIPOLYSIS HSL is active with a PO4 HSL is inactive without a PO4 In MUSCLE Lipids are used for fuel in the form of KETONE BODIES and FATTY ACIDS The importance of Carnitine is that it gets Fatty Acids into the mitochondria for oxidation MUSCLE LIPID METABOLISM IN FATTY ACID OXIDATION KETOSIS Regulation of oxidation in MITOCHONDRIA Stimulated by Fasting Uncontrolled Diabetes Glucagon Epinephrine Endurance Training Inhibited by FED state into the mitochondria carnitine step lead to hypoglycemia Malonyl CoA Increased levels of Malonyl CoA during FAT synthesis will inhibit fat translocation Disease states that lead to carnitine deficiency and oxidation enzyme deficiencies which will Ketone Body Formation in MITOCHONDRIA of the LIVER from ACETYLY CoA Note Pathway for Ketone Body formation contains HMG CoA as an intermediate which is also in CHOLESTEROL SYNTHESIS 3 types of Ketone Bodies AcetoAcetate hydroxybutyrate Acetone Note Ketone bodies are formed in the Liver but aren t used by the Liver Once they are formed by the Liver they are transported by blood to extrahepatic tissues Note When Acetyl CoA formation from Fat Oxidation is overly active the excess Acetyl CoA is made into Ketone Bodies They are formed because there isn t enough Oxaloacetate and too much Acetyl CoA so the extra Acetyl CoA is made into Ketone bodies in the mitochondria of the Liver 2 Conditions for Ketone Formation Starvation Fasting Severe Prolonged Exercise Uncontrolled Diabetes Very High Fat Low Carb diet Function of Ketones Ketones are used for energy by extrahepatic tissues muscle brain during adapted starvation Note In the Extrahepatic Tissues Ketone Bodies are converted back into Acetyl CoA for use in the TCA cycle to make more energy Therefore Ketone Bodies can be used as a source of energy when Carbohydrates are low This also conserves blood glucose Note Ketones are acidic and over long periods of time such as in Uncontrolled Diabetes excess Ketones can cause KETOACIDOSIS which disrupts the bodies ACID BASE balance This can be FATAL PHOSPHOLIPID TRIACYLGLYCEROL SYNTHESIS lipogenesis In order to make Phospholipids TAGS you must form GLYCEROL 3 PO4 first REMEMBER Glycerol to Glycerol 3 PO4 in Liver because Glycerol Kinase is present DHAP to Glycerol 3 PO4 in Liver and Adipose Tissue via Glycerol 3 PO4 Dehydrogenase 3 4 CHOLESTEROL AND BILE ACID SYNTHESIS CHOLESTEROL made in the CYTOPLASM from Acetyl CoA Mainly Intestine and Liver Cyclopentanoperhydrophenanthrene Ring Know this for possible Extra Credit OH group denotes a Sterol not present in Steroids Function Component of Cell Membrane Synthesis of Bile Acids Synthesis of Steroid Hormones Synthesis All a cell needs to make cholesterol is CYTOSOL NUCLEUS SMOOTH ER Note Cholesterol is made from Acetyl CoA and Ketones are made from Acetyl CoA Ketones however are made in the Mitochondria and Cholesterol is made in the Cytoplasm Cholesterol is made mainly in the Intestine and Liver but it is synthesized by most tissues Cholesterol Synthesis uses HMG CoA as an intermediate which is also in Ketosis Major Rate Controlling enzyme is HMG CoA Reductase HMG CoA Reductase is controlled by FEEDBACK INHIBITION which isn t allosteric Inhibited by Cholesterol in Dietary Cholesterol only inhibits cholesterol synthesis in the Liver Bile Acids HMG CoA Reductase is controlled by Covalent Modification Inactive with a PO4 Active without a PO4 Favored by Insulin Inhibited by Glucagon HMG CoA Reductase can be inhibited by Statin Drugs such as Lovastatin Note HMG CoA Reductase can also be controlled by Sterol Regulatory Elemental Binding Protein SREBP SREBP is a transcription factor that controls the synthesis of HMG CoA Reductase 5 6 Note To Lower Cholesterol one could increase fecal excretion of Bile Acids By eating a diet high in Soluble Fiber fiber will bind to Bile Acids which are made from cholesterol Once the fiber binds to the Bile Acids they are excreted thus reducing the amount of Bile Acids being reabsorbed by the Liver A healthy person will then Bile Acid synthesis and Cholesterol synthesis to make more Bile Acids Since the in Cholesterol synthesis will be used to make Bile Acids to replace the ones excreted there won t be any cholesterol going into the circulation thus ultimately lowering Cholesterol levels Cholesterol Degradation Routes of Excretion Excreted in Feces as unabsorbed Cholesterol
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