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Chapter 5

Chapter 5. Lipids. Simple lipids Fatty acids Triacylglycerols, diacylglycerols, & monoacylglycerols Waxes Sterol esters Nonsterol esters. Compound lipids Phospholipids Phosphatidic acids Plasmalogens Sphingomyelins Glycolipids Lipoproteins. Introduction. Derived lipids.

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Chapter 5

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  1. Chapter 5 Lipids 2009 Cengage-Wadsworth

  2. Simple lipids Fatty acids Triacylglycerols, diacylglycerols, & monoacylglycerols Waxes Sterol esters Nonsterol esters Compound lipids Phospholipids Phosphatidic acids Plasmalogens Sphingomyelins Glycolipids Lipoproteins Introduction 2009 Cengage-Wadsworth

  3. Derived lipids Ethyl alcohol Introduction 2009 Cengage-Wadsworth

  4. Structure & Biological Importance • Lipids important in human nutrition: • Fatty acids • Triacylglycerols • Sterols & steroids • Phospholipids • Glycolipids 2009 Cengage-Wadsworth

  5. Fatty Acids • Straight hydrocarbon chain terminating with a carboxylic acid group • Fatty acid nomenclature • Delta () system - length, number/ position of double bonds • Double bonds counted from omega (methyl) end 2009 Cengage-Wadsworth

  6. Fatty Acids • Essential fatty acids • Linoleic acid & -linolenic acid • n-3 fatty acids • Hypolipidemic & antithrombotic effects • Fish oils are rich sources 2009 Cengage-Wadsworth

  7. Triacylglycerols (Triglycerides) • Trihydroxy alcohol (glycerol) to which 3 fatty acids are attached by ester bonds • Nomenclature: stereospecific numbering (sn) • Exist as fats or oils depending on nature of fatty acid components 2009 Cengage-Wadsworth

  8. Sterols & Steroids • Sterols • Monohydroxy alcohols with 4-ring core structure called cyclopentanoperhydrophenanthrene (steroid) nucleus • Cholesterol = animal sterol • Component of cell membranes • Precursor for steroids: bile acids, sex hormones, adrenocortical hormones, vitamin D 2009 Cengage-Wadsworth

  9. Phospholipids • Glycerophsphatides • Glycerol - core structure • Phosphatidic acid - building block • Usually have saturated FA in position 1 & unsaturated FA in position 2 • Biological roles of phospholipids • Cell membranes, source of compounds, cell functions 2009 Cengage-Wadsworth

  10. Phospholipids • Sphingolipids • 18-carbon amino alcohol sphingosine forms backbone • 3 subclasses: • Sphingomyelins - sphingophosphatides • Cerebrosides - glycolipids • Gangliosides - glycolipids 2009 Cengage-Wadsworth

  11. Glycolipids • Occur in medullary sheaths of nerves & in brain tissue • Cerebrosides • Ceramide linked to a monosaccharide unit • Gangliosides • Ceramide linked to an oligosaccharide 2009 Cengage-Wadsworth

  12. Digestion • Triacylglycerol digestion • Lingual & gastric lipases • Emulsification in the stomach • Emulsification in small intestine - bile • The role of colipase • Pancreatic lipase activation 2009 Cengage-Wadsworth

  13. Digestion • Cholesterol & phospholipid digestion • Esterified cholesterol undergoes hydrolysis to free cholesterol & a FA • C-2 FA of lecithin hydrolytically removed to produce lysolecithin & a free FA 2009 Cengage-Wadsworth

  14. Absorption • Micelles interact at brush border & lipid contents diffuse out into enterocytes • FA > 10-12 C long re-esterified • Short-chain FA exit into portal blood 2009 Cengage-Wadsworth

  15. Transport & Storage • Topics related to transport & storage: • Lipoproteins • Role of the liver & adipose tissue • Metabolism of lipoproteins 2009 Cengage-Wadsworth

  16. Lipoproteins • Apolipoproteins • Protein components • Chylomicrons • Transport exogenous dietary lipids • Very-low-density lipoprotein (VLDL) & low-density lipoproteins (LDL) • Transport endogenous lipids 2009 Cengage-Wadsworth

  17. Role of the Liver & Adipose Tissue in Lipid Metabolism • Liver • Synthesizes bile salts • Synthesizes lipoproteins • Syntehsizes new lipids from non-lipid precursors • Adipose tissue • Absorbs TAG & cholesterol from chylomicrons through lipoprotein lipase • Stores TAG 2009 Cengage-Wadsworth

  18. Role of the Liver & Adipose Tissue in Lipid Metabolism • Metabolism of triacylglycerol during fasting • Adipocytes - lipolysis, release FA into blood • Liver - produces ketone bodies, continues to synthesize VLDL & HDL 2009 Cengage-Wadsworth

  19. Metabolism of Lipoproteins • Low-density lipoprotein (LDL) • Transports cholesterol to tissues • Binds with LDL receptor on cells • The LDL receptor: structure & genetic aberrations • Mutant cells can’t bind efficiently; synthesize cholesterol to meet needs • Free cholesterol in the cell serves regulatory functions 2009 Cengage-Wadsworth

  20. Metabolism of Lipoproteins • Domains of LDL receptor • Domain 1 - furthest from membrane, contains NH2 terminal of receptor, & rich in cysteine residues • Domain 2 - made of 350 amino acids, possibly site of N-linked glycosylation • Domain 3 - immediately outside plasma membrane, site of O-linked glycosylation • Domain 4 - made of 22 hydrophobic amino acids • Domain 5 - COOH terminal end of protein that projects into the cytoplast 2009 Cengage-Wadsworth

  21. Metabolism of Lipoproteins • Types of LDL receptor abnormalities • Class 1 - no receptors synthesized • Class 2 - precursor synthesized but not processed properly; fail to move into Golgi apparatus • Class 3 - synthesized & processed, but processing faulty • Class 4 - receptors bind with LDL but can’t cluster in the coated pits 2009 Cengage-Wadsworth

  22. Metabolism of Lipoproteins • High-density lipoprotein (HDL) • Removes unesterified cholesterol from cells/other lipoproteins • Returns it to the liver for excretion in bile • Binds to receptors on hepatic and extra-hepatic cells • Cholesterol acyltransferase (LCAT) 2009 Cengage-Wadsworth

  23. Lipids, Lipoproteins, & Cardiovascular Disease Risk • Of interest regarding CVD: • Cholesterol • Saturated & unsaturated fatty acids • Trans fatty acids • Lipoprotein A • Apolipoprotein E 2009 Cengage-Wadsworth

  24. Cholesterol • High HDL + low LDL = healthy • Ratios of ApoA to ApoB used to assess CVD risk • Indiviuals respond differently to dietary cholesterol • Absorption or biosynthesis • Formation & receptor-mediated clearance of LDL • Rates of LDL removal & excretion 2009 Cengage-Wadsworth

  25. Saturated & Unsaturated Fatty Acids • Positive correlation with CVD • Total fat • Saturated FAs • Cholesterol • Trans fat 2009 Cengage-Wadsworth

  26. Saturated & Unsaturated Fatty Acids • Negative correlation with CVD: • Monounsaturated FAs • Polyunsaturated FAs (n-3 & n-6) • n-3 fatty acids • Interfere with platelet aggregation • Reduce release of cytokines • Reduce serum TAG concentration 2009 Cengage-Wadsworth

  27. Saturated & Unsaturated Fatty Acids • Proposed mechanisms for effects of FAs: • Suppression of bile acid excretion • Enhanced synthesis of cholesterol & LDL • Retardation of LCAT activity or receptor-mediated LDL uptake • Regulation of gene expression 2009 Cengage-Wadsworth

  28. Trans Fatty Acids • Large amounts created through hydrogenation of PUFA • Most abundant: elaidic acid & its isomers • Raise LDL & cholesterol & lower HDL 2009 Cengage-Wadsworth

  29. Lipoprotein A [Lp(a)] • Genetic variant of LDL • Attached to a unique marker protein • Associated with atherosclerosis • Apo(a) is structurally similar to plasminogen 2009 Cengage-Wadsworth

  30. Apolipoprotein E • ApoE may be involved in atherogenesis • 3 isoforms: apoE2, -E3, E4 • E4 phenotype associated with increased CVD risk 2009 Cengage-Wadsworth

  31. Integrated Metabolism in Tissues • Catabolism of tracylglycerols & fatty acids • Mitochondrial transfer of acyl CoA • -oxidation of fatty acids • Energy considerations in fatty acid oxidation • Cleavage of saturated C-C yields 5 ATPs 2009 Cengage-Wadsworth

  32. Integrated Metabolism in Tissues • Formation of ketone bodies • Overflow pathway for acetyl CoA • Ketone concentration rises during accelerated FA oxidation + low CHO intake or impaired CHO use • Catabolism of cholesterol • Structure remains intact 2009 Cengage-Wadsworth

  33. Integrated Metabolism in Tissues • Synthesis of fatty acids • Basic process: sequential assembly of “starter” acetyl CoA with units of malonyl CoA • Essential fatty acids • Humans can’t introduce double bond beyond 9 site • Lack 12 & 15 desaturases 2009 Cengage-Wadsworth

  34. Integrated Metabolism in Tissues • Eicosanoids: fatty acid derivatives of physiological significance • Precursor arachidonate • “Cyclic” pathway (prostaglandins & thromboxanes) • “Linear” pathway (leukotrienes) • Prostaglandins - 20-C FAs with 5-C ring • Prostaglandins & thromboxanes are “hormone-like” in action • Leukotrienes - potent biological actions 2009 Cengage-Wadsworth

  35. Integrated Metabolism in Tissues • Essential fatty acid in development • Impact of diet on fatty acid synthesis • Synthesis of triacylglycerols • Synthesis of cholesterol • Cytoplasmic sequence • Conversion of HMG CoA to squalene • Formation of choleterol from squalene 2009 Cengage-Wadsworth

  36. Regulation of Lipid Metabolism • Linked to CHO status • Insulin’s presence or absence • Hormone-sensitive triacylglycerol lipase - mobilizes fat • Hormones that stimulate lipolysis • Acetyl CoA carboxylase 2009 Cengage-Wadsworth

  37. Brown Fat Thermogenesis • Brown adipose tissue - high vascularity, abundant mitochondria • Special mitochondria promote thermogenesis at expense of ATP • Have H+ pores in inner membranes formed of uncoupling protein (UCP) • Thermogenesis triggered by ingestion of food or prolonged exposure to cold temperatures 2009 Cengage-Wadsworth

  38. Therapeutic Inhibition of Fat Absorption: Olestra & Orlistat • Orlestra • Synthetic, non-caloric fat replacement • Orlistat • Interferes with digestion & absorption of dietary fat - 200 kcal deficit • Semisynthetic derivative of lipstatin • Inhibits pancreatic lipase 2009 Cengage-Wadsworth

  39. Ethyl Alcohol: Metabolism & Biochemical Impact • The alcohol dehydrogenase (ADH) pathway • ADH in liver cells - NAD+-requiring dehydrogenase - oxidizes ethanol to acetaldehyde • The microsomal ethanol oxidizing system (MEOS) • System of electron transport associated with SER • Tolerance - ethanol induces synthesis of MEOS enzymes 2009 Cengage-Wadsworth

  40. Ethyl Alcohol: Metabolism & Biochemical Impact • Alcoholism: biochemical & metabolic alterations • Acetaldehyde toxicity • High NADH:NAD+ ratio • Accumulation of lipids & lactate • Substrate competition • Vitamin A • Induced metabolic tolerance 2009 Cengage-Wadsworth

  41. Ethyl Alcohol: Metabolism & Biochemical Impact • Alcohol in moderation: the brighter side • Elevates HDL • Lowers serum lipoprotein • May suppress proliferation of smooth muscle cells underlying the endothelium of arterial walls 2009 Cengage-Wadsworth

  42. Perspective 5 The Role of Lipids & Lipoproteins in Atherogenesis 2009 Cengage-Wadsworth

  43. Lipids/Lipoproteins in Atherogenesis • Major components of atherogenesis: • Cells of the immune system • Oxidized or otherwise modified lipids & lipoproteins (LDL) • Roles of LDL • Chemoattractant for blood-borne monocytes • Causes transformation of monocytes into macrophages • Inhibits mobility of macrophages so they are trapped in endothelial spaces 2009 Cengage-Wadsworth

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