HUN3224 SUMMER 2013 Lipid Metabolism in the Liver Variations Among Tissues De novo synthesis of fatty acids fatty acid synthesis from non fat substances Glycerol 3 PO4 formed from o Glycerol via glycerol kinase phosphorylates Glycerol requires ATP o DHAP an intermediate in Glycolysis Glycerol 3 PO4 DHAP via Glycerol 3 PO4 dehydrogenase NADH used NADH H NAD Cholesterol synthesis Synthesis of VLDL s and HDL s Lipid Metabolism in the Adipose Tissue Major function storage of fat Diets which promote fat synthesis Triacylglycerol Synthesis lipogenesis o High energy o High carbohydrate o These promote fat synthesis because an increase in Glucose leads to an increase in Insulin Insulin favors storage of excess Glucose for fat synthesis Glucose pre cursor for fatty acid synthesis o Glycerol 3 PO4 must be formed from DHAP adipose tissue lacks glycerol kinase because it lacks glycerol kinase some of the glycerol will go into circu lation and into the kidney lactating mammary gland etc because they have glyc erol kinase o TAG synthesis increased by Insulin insulin enters tissues via Glut 4 glycolysis is occurring in tissue to produce DHAP Glycerol 3 PO4 The addition of 3 Fatty acyl CoA s to Glycerol 3 PO4 forms TAG s Hydrolysis of Triacylglycerol lipolysis into FA Glycerol o Catalyzed by Hormone Sensitive Lipase HSL Not catalyzed by LPL lipoprotein lipase anymore because lipoproteins have already delivered TAG s into tissue so now we need to break the TAG s down o HSL regulated covalently Stimulated by Catecholamines epinephrine norepinephrine glucagon adrenocorticotrophic hormone ACTH growth hormone GH cAMP is activated cAMP dependent protein kinase phosphory lates HSL activating it Methyl xanthines caffeine inhibits phosphodiesterase from in hibiting cAMP breakdown so cAMP cascade occurs o Phosphodiesterase breaks down cAMP and stops cAMP cascade HSL not phosphorylated inactive so methyl xanthines inhibit the enzyme Inhibited by Insulin Insulin will promote dephosphorylation of HSL by pro tein lipase stimulates protein lipase and phosphodiesterase HUN3224 SUMMER 2013 Explanation of Chart High energy diet leads to increase in Glucose which leads to an increase in Insulin promotes storage of fat and stimulates Glut 4 Glucose then undergoes Glycolysis Glucose 6 PO4 can undergo Glycolysis to form pyru vate or DHAP Pyruvate Acetyl CoA DHAP Glycerol 3 PO4 OR Glucose can enter HMP shunt to regenerate NADH for fatty acid synthesis to convert to Acyl CoA Acyl CoA from HMP shunt and Glycerol 3 PO4 from DHAP can esterify into triglycerides TAG s undergo hydrolysis lipolysis by HSL in Adipose Tissue Glycerol FA s formed Glycerol enters circulation HSL active with PO4 inhibited by insulin stimulates phosphodiesterase breaks down cAMP and stimulates protein lipase cleaves phosphate Caffeine tea will also degrade phos phodiesterase The FA s made from hydrolysis are composed of 2 pools one that is being produced by lipoly sis and one that is from the FA that went into circulation These FA pools can go back into adipose tissue from lipolysis or circulation to be broken into Acyl CoA Sometimes the rate of esterification formation of TAG s cannot keep up with the rate of lipol ysis hydrolysis of TAG s into Glycerol FA s this leads to more FA s in blood circulation which will then be transported to the liver and undergo TAG synthesis leading to fatty liver this happens in cases of uncontrolled diabetes excessive alcohol intake etc To oxidize alcohol NADH is necessary NADH gets depleted if excess alcohol is con sumed leading to fatty liver and sclerosis Phospholipid and Triacylglycerol Synthesis Formation of Glycerol 3 PO4 From Glycerol via glycerol kinase in liver only remember not in adipose tissue or muscle because kinase isn t present or has very low activity From DHAP in liver adipose tissue Formation of Phosphatidic Acid a common intermediate in TAG and phospholipid synthesis Step 1 same for TAG s and Phospholipids Glycerol 3 PO4 2 fatty acyl CoA s phosphatidic acid via acyltransferase HUN3224 SUMMER 2013 phosphatidic acid can also be referred to as phosphotidate or 1 2 Diacylglycerol phosphate Step 2 same for TAG s and Phospholipids Phosphatidic Acid 1 2 Diacylglycerol via phosphotidate phosphoshydrolase cleav age of phosphate Step 3 different for TAG s and Phospholipids Unique to TAG Unique to Phospholipids TAG s rate limiting step for TAG DAGH Diacyl glycerol trans ferase delivers fatty acyl CoA the first 2 fatty acyl CoA s were added in first step to form Triacyl glycerol the CoA is released Phospholipids First 1 2 Diacyl glycerol is acti vated by phos phorylation by ATP CTP Cytidine Then is linked to triphosphate to form CDP dephosphorylation CDP reacts with choline dephosphorylation to form CMP Phosphatidylcholine is formed Another way to make Phosphatidylcholine via Phospholipids SAM donates Methyl group 3 times HUN3224 SUMMER 2013 Phospholipids according to Nitrogenous Bases Phosphatidylcholine Phosphatidylserine o Can be formed by adding a residue of serine phos phatidylethanolmine Phosphatidylinositol Phosphatidylethanolamine plays role in most phospholipid synthesis Cholesterol and Bile Acid Synthesis Structure of Cholesterol know full name for possible extra credit Cyclopentanoperhydrophenanthrene Ring OH group that cholesterol contains is not present in steroids Functions of Cholesterol Component of cell membrane bilayer Precursor for bile acid synthesis Synthesis of steroid hormones Precursor for vitamin D 7 dehydrocholesterol Cholesterol Synthesis Occurs in almost all cells especially the liver intestinal cells o The cell MUST have a nucleus cytosol because that s where synthesis oc curs and a smooth endoplasmic reticulum for cholesterol synthesis to oc cur Takes place in cytosol cytoplasm 10 of all in liver intestine Made from HMG CoA is Rate controlling tosis ductase cholesterol is synthesized Acetyl CoA an intermediate also in ke enzyme HMG CoA re So if ketone bodies cholesterol are both made from Acetyl CoA and both have HMG CoA as an intermediate what s the different between them WHERE synthesis takes place o Mitochondria for ketone bodies o Cytosol for cholesterol Ketone synthesis occurs in mitochondria because this is where Oxidation takes place Cholesterol synthesis Stage 1 know ENTIRE stage 1 all details etc Stage 1 synthesis of Mevalonate 6C from 3 acetyl CoA s 2C 2 Acetyl CoA Acetoacetyl CoA via thiolase Thiolase combines 2 Acetyl CoA together 1 CoA is released so only 1 CoA
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