Post on 28-Dec-2015
2009 Cengage-Wadsworth
Chapter 5
Lipids
2009 Cengage-Wadsworth
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 > 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 can’t 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 can’t 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 can’t 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• Insulin’s 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 NADH:NAD+ 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