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Chapter 5
Lipids
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Introduction
• Simple lipids
• Compound lipids
– Fatty acids
– Triacylglycerols,
diacylglycerols, &
monoacylglycerols
– Waxes
• Sterol esters
• Nonsterol esters
– 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
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