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Lipid Metabolism

Lipid Metabolism. Lipid Transport in Blood. Lipids are not water soluble Blood is mainly water… Pack lipids in protein Chylomicrons Made in the enterocytes (small intestine) Lipoproteins (lipids and proteins) VLDL, LDL, HDL made in liver. Groff & Gropper, 1999.

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Lipid Metabolism

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  1. Lipid Metabolism

  2. Lipid Transport in Blood • Lipids are not water soluble • Blood is mainly water… • Pack lipids in protein • Chylomicrons • Made in the enterocytes (small intestine) • Lipoproteins(lipids and proteins) • VLDL, LDL, HDL made in liver Groff & Gropper, 1999

  3. Release of Lipids at Liver • Chylomicrons  chylomicron remnants • Cholesterol-rich • Taken up by liver and fatty acids are metabolized

  4. Repackaging in the Liver • Lipid is repackaged in the liver to VLDL or very low density lipoprotein • Lipoproteins are classified by density • Lipoproteins transport lipid to the rest of the body TG TG VLDL LDL HDL

  5. Lipoproteins • Classified by density • Protein:lipid ratio • More protein, increased density • More lipid, decreased density • Four classes of lipoproteins • Chylomicrons • VLDL • LDL • HDL Formed in liver

  6. Lipoproteins • Differ according to the lipid:protein ratio • Density • Chylomicrons • Very-low–density lipoproteins (VLDL) • High lipid content • Low-density lipoproteins (LDL) • Main cholesterol transport • High-density lipoproteins (HDL) • Low lipid content Low High

  7. aTriacylglycerols, bPhospholipids, cCholesteryl esters, dFree cholesterol, eFree fatty acids*HDL2 and HDL3 derived from nascent HDL as a result of the acquisition of cholesteryl esters

  8. Low Density Lipoproteins • VLDL   LDL • Cholesterol-rich • Converted to bile salts • Carries cholesterol to tissues • Used for membrane synthesis • LDL ~ ‘bad cholesterol’ • Associated with plaque formation in blood vessels • High triglyceride and cholesterol content

  9. High Density Lipoproteins • Removes cholesterol from: • Cells • Lipoproteins • Deliver cholesterol to liver for excretion • Converted to bile salts and excreted in feces • HDL ~ ‘good cholesterol’ • Is cholesterol ‘bad’ for you? • Cell membranes, bile salts, synthesis of steroid hormones • Ratio of LDL:HDL vs. total cholesterol

  10. Lipid Transport • Free fatty acids transported as complex with albumin in blood • Lipids rapidly removed from blood • Liver • Fat depots • Other tissue

  11. Release of Lipids From Lipoproteins • Lipoprotein lipase (LPL) • Enzyme anchored on the cell membranes in blood vessels • Releases glycerol and free fatty acids from chylomicrons and lipoproteins • Glycerol and free fatty acids absorbed by cells • Muscle (oxidized as a source of energy)

  12. Lipolysis – Monogastric & Ruminant • Mobilization of body triglycerides for use as energy Lipoprotein Lipase + Triglyceride Glycerol 3 FFA * Gluconeogenesis Β-oxidation Glycolysis * Free fatty acids bind to albumin to form non-esterified fatty acids that are soluble in blood

  13. Triglyceride Catabolism • Hydrolysis of triglycerides yields • One glycerol • Three FFA • Glycerol is used for energy or gluconeogenesis • Glycerol enters glycolytic pathways • FFA are oxidized to CO2 and H2O • -oxidation • Takes place in mitochondria • FA’s cannot be used for gluconeogenesis

  14. Beta Oxidation

  15. O CH3–C–CoA = β-oxidation – Saturated Fatty Acids • Cleaves two carbons at a time from the carboxyl end • Produces NADH, FADH2 and acetyl-CoA • Acetyl-CoA enters TCA cycle • NADH and FADH2 enter electron transport chain • Yield ATP

  16. 1st Step in Beta-Oxidation Activation: Use 2ATP equivalents to attach CoA Oxidation: FAD takes H, Creates new double bond between C 2 & 3 Hydration: add water across double bond Oxidation: NAD takes H’s, new O= formed Addition & Cleavage: Add new CoA, cleave off acetyl-CoA. Lose 2 C

  17. -Oxidation 1st 2nd 3rd 4th 5th 6th last • Palmitate (16:0) • Carbon–carbon cleavage • 1 FADH2 + 1 NADH  5 ATP (via electron transport chain) • 7 cleavage points x 5 ATP = 35 ATP • Oxidation of acetyl–CoA • 8 acetyl-CoA units entering TCA cycle x 12 ATP = 96 ATP • Total ATP  35 + 96 = 131 – 2 ATP = 129 ATP • 2 ATP used for fatty acid activation and entry into mitochondria

  18. Summary of β-oxidation

  19. Special Considerations • Why doesn’t muscle utilize fatty acids during exercise? • Requires oxygen available for oxidation • Use anaerobic fermentation of glucose to lactate preferentially • Why don’t red blood cells utilize fatty acids for their energy metabolism? • No mitochondria in RBC’s

  20. Unsaturated Fatty Acids • Unsaturated fatty acids must be saturated before beta-oxidation • Isomerase converts cis to trans and moves double bond to the 2 position • In polyunsaturated: need reductase • Add H’s to second double bond

  21. Odd Chain Fatty Acids • Minor species, odd chains made by microbes, degradation of AA’s • B-oxidation occurs to end: • Left with 3 carbon + CoA (propionyl CoA) • Vitamin B12 cobalamin co-enzyme • Catalyzes conversion of propionyl CoA (3 C) to succinyl-CoA (4 C) • TCA cycle intermediate

  22. Ketone Bodies (Ketogenesis) • Acetone, acetoacetate, β-hydroxybutyrate • Produced in liver from incomplete oxidation of fatty acids • Used by extra-hepatic (non-liver) tissue in preference to fatty acids as energy • Turned into acetyl-CoA • Excess spills over into urine or exhaled as acetone

  23. Metabolismof Fats Metabolism of natural C20 cis fatty acids produces powerful eicosanoids

  24. Cyclooxygenase (COX) Inhibitors • Cyclooxygenase has 3 isoforms (COX-1, COX-2, and COX-3) • Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit these pathways • Aspirin and ibuprofen are classic examples • Acetaminophen is NOT an NSAID because it does not inhibit inflammatory pathways • Specifically inhibits COX-3 which produces prostanoids in the brain – so it blocks the perception of pain

  25. Fatty Acid Synthesis • In fed state - lots of glucose • Glycogen stores fill up • ATP and citrate inhibit glycolysis pathways • Glucose diverted through the pentose-phosphate pathway • NADPH formed and used in fatty acid synthesis • Pyruvate is formed

  26. Fatty Acid Synthesis - Monogastrics • What are the advantages of storing excess feed or energy as fat? • High energy density tissue, low water content • Major producers of fatty acids • Liver • Adipose tissue • Mammary gland • Can animals synthesize all fatty acids? • NO – essential fatty acids MUST come from diet • C18:2, C18:3 • Cats cannot synthesize C20:4

  27. Fatty Acid Biosynthesis - Monogastric • Occurs in endoplasmic reticulum • Occurs when: • Energy needs are met (ATP > ADP) • Glycogen stores full • Excess nutrients present

  28. Fatty Acid Biosynthesis - Monogastric • Begins with acetyl-CoA from: • Carbohydrate metabolism (glucose) • Specific amino acids • Degraded lipids • Fatty acid chains are created • 2C units added from carboxyl to methyl end • Ester bonds • Up to 16C (palmitate) fatty acids can be synthesized • NADPH required as “energy source”

  29. Acetyl CoA TCA Cycle Citrate Mitochondria Cytosol Citrate Oxaloacetate HCO3 ATP (2C) Acetyl CoA (3C) Malonyl CoA Acetyl CoA Carboxylase(biotin) CO2 Fatty Acid Synthase NADPH 4C Butyryl CoA 2C Acetyl CoA 3C Malonyl CoA CO2 NADPH 6C Caprayl CoA

  30. Fatty Acid Biosynthesis - Monogastric • Cycle continues by continued addition of malonyl CoA and loss of CO2 • Palmitate (16C) is final product after 7 cycles • Desaturation and elongation occur elsewhere: ER

  31. Fatty Acid Modifications • Palmitate can be elongated • Addition of two-carbon units at COOH-end of fatty acid • Desaturation • C16:0 and C18:0 can be converted to C16:1 and C18:1, respectively

  32. Mammals lack enzyme to add double bonds beyond C-9 Chain elongation and double bond addition yield arachidonic acid (C20:4) from linoleic acid (C18:2) Why are w-3 & w-6 Essential?

  33. Lipid Synthesis in Monogastrics Figure 25.10

  34. Lipogenesis - Ruminants • Similar to monogastrics except for: • Sources of carbon (acetyl-CoA) • Acetate • Lactate • Beta-hydroxy-butyrate • Dietary fatty acids Unable to convert glucose to fatty acids

  35. Adipose Tissue • Adipocytes are the major storage site for triglycerides • Adipose tissue (stored for later use, or immediately oxidized as a source of energy) • Contains up to approximately 85% lipid • Contains approximately 90% DM • What is the DM content of muscle? • Only 20-25% DM!!!

  36. Change in size = amount of fat stored • Obesity = increase in both size and number • MS, Lupus & other diseases = normal tissue dies, replaced by fibroblasts, become adipocytes

  37. Adipose Tissue Fed state... Groff & Gropper, 1999

  38. Adipose Tissue • Fasted state • Blood glucose level decreases insulin levels decrease and glucagon levels increase • Lipolytic activity increases • Hormone-sensitive lipase • Release of fatty acids • Free fatty acids released into blood • Free fatty acid–albumin complex • Liver takes up free fatty acids • Oxidation or formation of ketone bodies

  39. Leptin • Protein hormone produced by adipocytes • Larger cells = more leptin produced • Effects on many tissues • Hypothalamus • Regulates eating behavior • Negative-feedback mechanism

  40. Leptin-deficient mutants (left) fail to limit their eating and becomes 3 times the weight of normal mouse (right)

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