HUN3224 SUMMER 2013Variations Among TissuesLipid Metabolism in the Liver· 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 ATPo 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’sLipid Metabolism in the Adipose Tissue· Major function = storage of fat· Diets which promote fat synthesiso High energyo High carbohydrateo 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 = precursor for fatty acid synthesis)· Triacylglycerol Synthesis (lipogenesis)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 circulation and into the kidney, lactating mammary gland etc. because they have glycerol kinaseo 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 + Glycerolo 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 downo HSL regulated covalently Stimulated by:· Catecholamines (epinephrine & norepinephrine), glucagon, adrenocorticotrophic hormone (ACTH), growth hormone (GH): cAMP is activated cAMP dependent protein kinase phosphorylates HSL, activating it· Methyl xanthines (caffeine): inhibits phosphodiesterase from inhibiting cAMP breakdown so cAMP cascade occurso 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 protein lipase (stimulates protein lipase and phosphodiesterase)HUN3224 SUMMER 2013Explanation of ChartHigh energy diet leads to increase in Glucose which leads to an increase in Insulin; promotes storage of fat and stimulates Glut 4Glucose then undergoes Glycolysis; Glucose-6-PO4 can undergo Glycolysis to form pyruvate or DHAP-Pyruvate Acetyl CoA- DHAP Glycerol-3-PO4OR, Glucose can enter HMP shunt to regenerate NADH (for fatty acid synthesis) to convert to Acyl CoAAcyl CoA (from HMP shunt) and Glycerol-3-PO4 (from DHAP) can esterify into triglyceridesTAG’s undergo hydrolysis (lipolysis by HSL) in Adipose Tissue; Glycerol + FA’s formedGlycerol enters circulationHSL (active with PO4) inhibited by insulin (stimulates phosphodiesterase: breaks down cAMP and stimulates protein lipase: cleaves phosphate). Caffeine/tea will also degrade phosphodiesterase.The FA’s made from hydrolysis are composed of 2 pools one that is being produced by lipolysis and one that is from the FA that went into circulationThese 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 lipolysis (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 consumed, leading to fatty liver and sclerosisPhospholipid and Triacylglycerol SynthesisFormation 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 synthesisStep 1 (same for TAG’s and Phospholipids)Glycerol-3-PO4 + 2 fatty acyl-CoA’s phosphatidic acid via acyltransferaseHUN3224 SUMMER 2013**phosphatidic acid can also be referred to as phosphotidate or 1,2-Diacylglycerol phosphateStep 2 (same for TAG’s and Phospholipids)Phosphatidic Acid 1,2-Diacylglycerol via phosphotidate phosphoshydrolase (cleavage of phosphate)Step 3 (different for TAG’s and Phospholipids) Unique to TAG Unique to PhospholipidsTAG’s**rate limiting step for TAG· DAGH (Diacylglycerol transferase) delivers fatty acyl-CoA (the first 2 fatty acyl-CoA’s were added in first step) to form Triacylglycerol (the CoA is released)Phospholipids· First, 1,2-Diacylglycerol is activated by phosphorylation by ATP· Then, is linked to CTP (Cytidine triphosphate) to form CDP (dephosphorylation)· CDP reacts with choline (dephosphorylation) to form CMP· Phosphatidylcholine is formedAnother way to make Phosphatidylcholine (via Phospholipids)· SAM donates Methyl group 3 timesHUN3224 SUMMER 2013Phospholipids according to Nitrogenous Bases· Phosphatidylcholine· Phosphatidylserineo Can be formed by adding a residue of serine + phosphatidylethanolmine· Phosphatidylinositol· Phosphatidylethanolamine plays role in most phospholipid synthesisCholesterol and Bile Acid SynthesisStructure of Cholesterol**know full name for possible extra credit Cyclopentanoperhydrophenanthrene Ring**OH group that cholesterol contains is not present in steroidsFunctions 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 cellso The cell MUST have a nucleus, cytosol (because that’s where synthesis occurs) and a smooth endoplasmic reticulum for cholesterol synthesis to occur· Takes place in cytosol (cytoplasm)· 10% of all cholesterol is synthesized in liver/intestine· Made from Acetyl-CoA· HMG-CoA is an intermediate (also in ketosis)· Rate controlling enzyme HMG-CoA reductaseSo, 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 placeo Mitochondria for ketone bodieso Cytosol for cholesterol· Ketone
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