Lipids

1
Chapter 5

• Lipids

2
Introduction

• Simple lipids
• Fatty acids
• Triacylglycerols, diacylglycerols,
  monoacylglycerols
• Waxes
• Sterol esters
• Nonsterol esters

• Compound lipids
• Phospholipids
• Phosphatidic acids
• Plasmalogens
• Sphingomyelins
• Glycolipids
• Lipoproteins

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Introduction

• Derived lipids

• Ethyl alcohol

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Structure Biological Importance

• Lipids important in human nutrition
• Fatty acids
• Triacylglycerols
• Sterols steroids
• Phospholipids
• Glycolipids

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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

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Fatty Acids

• Essential fatty acids
• Linoleic acid ?-linolenic acid
• n-3 fatty acids
• Hypolipidemic antithrombotic effects
• Fish oils are rich sources

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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

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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

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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

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Phospholipids

• Sphingolipids
• 18-carbon amino alcohol sphingosine forms
  backbone
• 3 subclasses
• Sphingomyelins - sphingophosphatides
• Cerebrosides - glycolipids
• Gangliosides - glycolipids

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Glycolipids

• Occur in medullary sheaths of nerves in brain
  tissue
• Cerebrosides
• Ceramide linked to a monosaccharide unit
• Gangliosides
• Ceramide linked to an oligosaccharide

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Digestion

• Triacylglycerol digestion
• Lingual gastric lipases
• Emulsification in the stomach
• Emulsification in small intestine - bile
• The role of colipase
• Pancreatic lipase activation

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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

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Absorption

• Micelles interact at brush border lipid
  contents diffuse out into enterocytes
• FA gt 10-12 C long re-esterified
• Short-chain FA exit into portal blood

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Transport Storage

• Topics related to transport storage
• Lipoproteins
• Role of the liver adipose tissue
• Metabolism of lipoproteins

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Lipoproteins

• Apolipoproteins
• Protein components
• Chylomicrons
• Transport exogenous dietary lipids
• Very-low-density lipoprotein (VLDL) low-density
  lipoproteins (LDL)
• Transport endogenous lipids

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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

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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

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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 cant bind efficiently synthesize
  cholesterol to meet needs
• Free cholesterol in the cell serves regulatory
  functions

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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

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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 cant
  cluster in the coated pits

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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)

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Lipids, Lipoproteins, Cardiovascular Disease
Risk

• Of interest regarding CVD
• Cholesterol
• Saturated unsaturated fatty acids
• Trans fatty acids
• Lipoprotein A
• Apolipoprotein E

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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

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Saturated Unsaturated Fatty Acids

• Positive correlation with CVD
• Total fat
• Saturated FAs
• Cholesterol
• Trans fat

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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

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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

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Trans Fatty Acids

• Large amounts created through hydrogenation of
  PUFA
• Most abundant elaidic acid its isomers
• Raise LDL cholesterol lower HDL

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Lipoprotein A Lp(a)

• Genetic variant of LDL
• Attached to a unique marker protein
• Associated with atherosclerosis
• Apo(a) is structurally similar to plasminogen

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Apolipoprotein E

• ApoE may be involved in atherogenesis
• 3 isoforms apoE2, -E3, E4
• E4 phenotype associated with increased CVD risk

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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

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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

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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 cant introduce double bond beyond ?9 site
• Lack ?12 ?15 desaturases

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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

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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

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Regulation of Lipid Metabolism

• Linked to CHO status
• Insulins presence or absence
• Hormone-sensitive triacylglycerol lipase -
  mobilizes fat
• Hormones that stimulate lipolysis
• Acetyl CoA carboxylase

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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

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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

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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

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Ethyl Alcohol Metabolism Biochemical Impact

• Alcoholism biochemical metabolic alterations
• Acetaldehyde toxicity
• High NADHNAD ratio
• Accumulation of lipids lactate
• Substrate competition
• Vitamin A
• Induced metabolic tolerance

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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

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Perspective 5

• The Role of Lipids Lipoproteins in Atherogenesis

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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