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Post-Absorptive Lipid Metabolism

Post-Absorptive Lipid Metabolism. Lipid Metabolism Terms. Lipogenesis Making of fat from dietary fat or dietary CHO Lipolysis Breaking down of fat: GIT, capillary and adipocyte De Novo lipogenesis Making of fat from CHO (takes place in liver and adipocyte)

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Post-Absorptive Lipid Metabolism

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  1. Post-Absorptive Lipid Metabolism

  2. Lipid Metabolism Terms • Lipogenesis • Making of fat from dietary fat or dietary CHO • Lipolysis • Breaking down of fat: GIT, capillary and adipocyte • De Novo lipogenesis • Making of fat from CHO (takes place in liver and adipocyte) • Fat exported from liver as VLDL (very low density lipoprotein) • Pancreatic lipase • Breaks down TG’s in GIT • Lipoprotein Lipase • Breaks down TG’s from chylomicron and VLDL in the capillary • -oxidation: • Breaking down of fatty acids into acetyl-CoA • Hormone Sensitive Lipase • Breaks down TG’s within the adipocyte • NEFA • Non-esterified fatty acids: fatty acids mobilized (exiting) the adipocyte

  3. Lipid Metabolism

  4. Lipid Absorption

  5. Plasma Lipid • Transported in two primary vesicles: • Chlyomicrons • From intestine • Packages dietary lipid • Very Low Density Lipoprotein (VLDL) • From the liver • Packages: • Fatty acids derived from excess carbohydrates • Fatty acids taken up from circulation

  6. 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

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

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

  9. 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

  10. 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

  11. VLDL • = Very Low Density Lipoprotein • Made in: the liver from excess dietary carbohydrate and protein along with the Chylomicron remnant • Secreted into: the bloodstream • Rich in: TGs • Function: Deliver TGs to body cells • Contains apo B100 • Similar to Chylomicrons, but made by different tissues

  12. LDL • = Low Density Lipoprotein • Made in: the Liver as VLDL • Arise from: VLDL once it has lost a lot of its TG’s • Secreted into: the bloodstream • Rich in: Cholesterol • Function: Deliver cholesterol to all body cells

  13. 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

  14. 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

  15. HDL • = High Density Lipoprotein • Made in: the Liver and Small Intestine • Secreted into: the bloodstream • Function: Pick up cholesterol from body cells and take it back to the liver = “reverse cholesterol transport” • Potential to help reverse heart disease

  16. Lipoprotein Nomenclature and Composition CM VLDL IDL LDL HDL Major apoB apoB apoB apoB apoA-I Protein Major TG TG CE CE CE Lipid CM= chylomicron TG=triglyceride VLDL= very low density lipoprotein CE= cholesteryl ester IDL= intermediate density lipoprotein LDL= low density lipoprotein HDL= high density lipoprotein Apo = apolipoprotein

  17. LDL Intestine apoCs VLDL apoCs apoE apoB-100 apoA-I apoA-I Nascent-HDL Nascent-HDL CM apoB-100 apoE apoB-48 IDL apoB-100 Liver Site of Synthesis of Lipoproteins

  18. 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

  19. Key Enzymes in Lipoprotein Metabolism • Lipoprotein lipase (LPL): hydrolysis of triglyceride rich particles • Lecithin:cholesterol acyltransferase (LCAT): participates in removal of excess cholesterol from peripheral cells

  20. Lipoprotein Lipase (LPL) Endothelial Cell LPL apoA-I apoC-II cholesterol Fatty Acids and Glycerol CM phospholipid Excess Surface Material VLDL apoE Lipolytic products CM Energy VLDL apoE “Remnant” HDL assembly Liver muscle Bile acids TG LDL TG = triglyceride

  21. 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)

  22. CE Cholesteryl ester (CE) Cholesterol Phospholipid ApoA-I Lecithin:Cholesterol Acyl Transferase (LCAT) LCAT: Disk to sphere transformation Free cholesterol Cholesteryl ester Mature HDL Nascent HDL LCAT apoA-I Phospholipid plus cholesterol Cholesteryl ester (CE) plus lysophospholipid

  23. 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

  24. 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

  25. Plasma Lipid Clearance Unlike glucose and amino acids, most lipids from a meal do not directly enter the bloodstream. Instead, they are packaged into chylomicrons and released into the lymph. The lymph dumps into the aortic arch (near the heart), where it then is transported through the bloodstream to be cleared (taken up) by: adipocytes muscle liver Thus, unlike carbohydrates and protein, most lipids do not use the enterohepatic circulatory system. This allows lipids to be cleared by the whole body and avoids overwhelming the liver with lipid. Clearance of lipid from circulation is mediated by adipose,muscle and liver: via the enzyme Lipoprotein Lipase (LPL)

  26. Regulation of Lipid metabolism • Well fed: •  Insulin   lipogenesis &  lipolysis • Starving: •  epinephrine/norepinephrine   lipolysis •  Insulin   lipolysis • Very Low CHO, high PTN diet: • No  Insulin   lipogenesis • No  Insulin   lipolysis

  27. Lipid Synthesis (lipogenesis) Creation of fat is via two primary routes • 1) De novo fatty acid synthesis • Process by which simple non-lipid nutrients are converted to long chain fatty acids and stored as triglycerides, especially in adipose tissue • Monogastrics: glucose is the major source of carbon for fatty acid synthesis • Ruminants: acetate is the major source of carbon for fatty acid synthesis • 2) Preformed uptake: incorporation of dietary fat • Most of human adipose is derived from diet • Both are stimulated by insulin

  28. De novo fatty acid Synthesis • Two Key Enzymes: • Acetyl CoA Carboxylase (ACC) • Rate limiting enzyme • Fatty Acid Synthase (FAS) • Animals on a high fat diet experience little if any de novo fatty acid synthesis • Typical western civilization diet is high in fat • agriculture species usually fed a high CHO diet • Fetal animals have large de novo activity

  29. De novo Fatty Acid Synthesis glucose Fatty Acids NADPH pyruvate FAS Acetyl Co A ACC TCA Citrate Acetyl Co A monogastrics ruminants Acetate

  30. Why glucose is not a C-source for fatty acid synthesis in ruminants • Limiting enzymes Citrate lyase Malate dehydrogenase • Use of glucose for fat synthesis • Supply NADPH • Synthesis of glycerol

  31. Acetyl CoA Carboxylase (ACC) Allosteric modification Activated by: Citrate Inhibited by: LCFA Covalent Modification Activated by: Dephosphorylation Inhibited by: Phosphorylation ACC

  32. FAS

  33. Fatty Acid Synthase (FAS) • 2nd and final step • Multifunctional polypeptide • High in the well-fed state • Not regulated by either allosteric or covalent modification • Regulated by the amount of [PTN] • High in fed-state • Low in fasting-state • Palmitate is usually the end product

  34. PPP NADPH FAS ATP Citrate Lyase

  35. Species comparison of fatty acid synthesis

  36. Preformed Fatty Acid Uptake • Dietary derived • Dietary TG packaged in chylomicrons • Liver derived • Either repackaged TG from chylomicron remnants or TG synthesized de novo and secreted as VLDL • TG in both are hydrolyzed by lipoprotein lipase (LPL) in capillary bed

  37. LPL action on TG rich lipoproteins Glycerol + 3 Fatty acids TG capillary Lipoprotein lipase Cell I.e. adipocyte muscle mammary Chylomicrons VLDL Fatty acids Triglycerides

  38. LPL Mediated Fatty Acid Uptake

  39. Lipid breakdown (lipolysis) • The breaking down (hydrolysis) of intracellular triglycerides • Can be reesterified or mobilized • Mobilization • Net release of fatty acids from adipocytes • NEFAs are transported in blood bound to albumin • Undergo -oxidation to produce acetyl CoA’s • Oxidized by energy needing cells • Stimulated by epinephrine AND the lack of insulin

  40. Triglyceride breakdown • Lipoprotein Lipase: found on endothelial (vessel) walls lining tissues such as adipose and muscle. Releases FFA from TAGs in CM/VLDL for cellular uptake and usage as either energy (muscle) or storage (adipocyte). Thus insulin & glucagon differentially regulate this enzyme on muscle vs. adipose cells. TAG 2-MAG + FFA cell • Hormone-sensitive lipase: Only found INSIDE adipocyte. Releases FFA from adipocyte TAG stores, sends to serum. Incr by glucagon, epinephrine. TAG 2-MAG + FFA serum • Regulation of LPL Activity: factor adipose muscle starvation down up Well Fed up down insulin up down

  41. Lipolysis Overview Epinephrine Fatty Acids Glycerol  Adenylate Cyclase  cAMP  Hormone Sensitive Lipase Triglyceride  Fatty acids + glycerol

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