This document discusses fatty acids, including polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), and the omega-3 and omega-6 families. It notes that PUFAs have at least two double bonds, are found in cellular membranes, and can be metabolized into inflammatory eicosanoids. Omega-3 and omega-6 PUFAs are essential fatty acids that must be obtained through diet. The document also discusses how PUFAs can impact membrane properties and immune cell function through lipid peroxidation and eicosanoid production.
1. Polyunsaturated fatty acids
• Cis configuration in nature
• Generally unsaturated fatty acids are confined to the sn-2 position of
phospholipids and are 18-20 carbons long
• MUFA tend to be in the sn-1 position, like saturated fats.
• Hydrocarbon portion is saturated or partially unsaturated
3,6-PUFA
9-MUFA
2. PUFA, MUFA
• Monounsaturated fatty acids (MUFA)- only one
double bond present
• Polyunsaturated fatty acids (PUFA)- at least 2
double bonds are present
• Acetylenic – one or more triple bonds
• Polyunsaturated/Monounsaturated
– Ex. Docosahexaenoic Acid, Oleic Acid
• Double bonds have a planar conformation
3. MUFA
• Most of the 100 MUFAs identified are rare
• Oleic acid is very abundant in nature
-most prevalent unsaturated fat in human
diet
-highest content in extra virgin olive oil (70g/
100g)
4.
5. 3 categories of PUFA
• Conjugated – if double bonds alternate with
single bonds (– C = C – C = C –)
• Unconjugated – of the double bonds are
separated by carbon atoms bonded with
single bonds (– C = C – C – C = C –)
• A third category exist in which double bonds are
not all entirely in the methylene interrupted
arrangement (present in certain microorganisms,
marine lipids and some seed oils.
6. Unconjugated most common
• Subdivided into
families, depending
on the position of
the double bond
closest to the
methyl side (),
numbered 1 on the
fatty acid chain.
• 12 omega families
• -3,6,9 are what’s
found in normal diet
7. -3 and -6 are Essential Fatty Acids
• Mammals lack the enzymes to introduce double
bonds at carbon atoms beyond C9.
• Hence, all fatty acids containing a double bond at
positions beyond C9 have to be supplied in the
diet.
• Linoleate (18:2 Δ 9,12) and Linolenate (18:3 Δ
9,12,15) are the two essential fatty acids in
mammals.
• Interconversion between PUFAs occur only
within the same family
8. Oleic Acid (OA): C18:1, n-9 or -9
Good source: Olive oil, Peanut oil,
Soy oil
Linoleic Acid (LA): C18:2, n-6 or
-6. Essential Fatty Acid
Alpha Linolenic Acid (ALA): C18-3,
n-3 or -3. Essential Fatty Acid
Good source: Flaxseed
9. Eicosapentaenoic Acid (EPA): C20:5, n-3 or -3. Essential
Fatty Acid. Good source: Fish oil
Docosahexaenoic Acid (DHA): C22:6, n-3 or -3.
Essential Fatty Acid. Good Source: Fish oil
Arachidonic Acid (AA): C20:4, n-6 or -6.
Good source: Liver, Beef.
10.
11. Omega-6 fatty acids
• Linoleic (C18:2) is
essential
• Found in:
-vegetable oil
-nuts and seeds
• Only need about a
tbsp/day
12. Omega-3 Fatty Acids
• primarily in fish and marine
mammals
• Also found in soybean, canola,
walnut, flaxseed oils
Recommended
omega6:omega-3
ratio is 2.3:1
14. • Anthropological research suggest that our hunter gatherer
ancestors consumed roughly 1:1 ratio of omega-6:omega 3.
• Vegetable oil consumption rose dramatically between the
beginning and end of the 20th century.
-Between 1935 and 1939, the ratio of n-6 to n-3 fatty acids
was reported to be 8.4:1
-Ratio increased to 10.3:1 by 1985
-Todays estimates range between 10:1 to 20:1
• Americans now get almost 20% of their calories from a single
food source – soybean oil – with almost 9% of all calories from
the omega-6 fat linoleic acid (LA) alone!
• recommended 30% of diet
-10% monounsaturated
-10% saturated
-10% unsaturated
15. How Can Fatty Acids Modulate the Immune
System?
• Membrane fluidity
• Lipid peroxidation
• inflammatory cytokines (IL-6, IL-12, IL-23)
production
• Eicosanoid production
• Membrane fusion and phagocytic activity
• Lymphocytic proliferation
• Immune cell migration
Fatty acids impact:
16. • Depending on diet, fatty acids end
up in plasma membrane
• Consumption of hydrogenated oils
results in reduction of PUFAs in
plasma membrane
• Most tissues contain mainly
omega-6 fatty acids (75% as LA
and AA), with small amounts of
omega-3 fatty acids
-the exception is retina, brain and
testes
17. 17
Eicosanoids: paracrine hormones
• Derived from the 20 carbon polyunsaturated fatty acid
(arachidonic acid)
• Involved in reproduction, inflammation, fever and pain
• 3 classes: Prostaglandins, thromboxanes, leukotrienes
Regulate synthesis of cAMP
production fever, pain,
blood flow, and uterine
contraction
Produced by
platelets,
important in
clotting and
blood flow
Inflammation,
asthma, allergy
18. Arachidonic Acid (AA): C20:4, n-6 or -6.
Good source: Liver, Beef.
Arachidonic Acid Metabolism
Eiscosanoids mainly formed from AA sincse it is
dominant in cell membrane and plasma lipids
Cleaved by phospholipases
Three pathways of eicosanoid production from AA:
1) COX: AA PG, TXs
2) LOX: AA HPETE and HETE LTs and lipoxins
3) Cytochrome P450: AA EET and DHET
NSAIDs inhibit the COX pathway
19. Eicosanoid action
• Released into extracellular fluid
• Bind to membrane receptors on target cell
• Binding causes signal transduction
• Main function is cell-cell communication
(paracrine)
• Can also act on itself (autocrine)
20. Phospholipid membrane
Phospholipase A2
Cyclooxygenases (COX)
Prostaglandins (PG)
&
Thromboxanes (TX)
Lipoxygenases (LOX)
Leukotrienes
O
HO
O
HO
Arachidonic acidEicosapentaenoic acid
• EPA ompetes with AA for incorporation into
the cell membrane
• poor substrate for cyclooxygenases
• gives rise to series 5 leukotrienes
21. DHA and Phosphatidylserine
• PS is a recognition marker for apoptotic cells
– It is highly prevalent in Brain tissue
– Made up of predominantly Stearic Acid (C18:0) and DHA (C22:6)
• PS predominantly resides on the interior (cytoplasmic side of
plasma membrane)
– Flippase is responsible for the assymetry
• Upon apoptosis, more of PS translocates to the exterior
facilitating uptake by scavenger cells such as macrophages and
neutrophils.
• Reduced levels of PS with DHA, may decrease efficiency
uptake by scavenger cells.
• Anecdotal evidence for preventing dementia
22.
23. • NF-B/IkB dimer resides
in cytosol
• Upon stimulation, IkB is
phosphorylated/degraded
• NF-B translocates to
nucleus facilitating
transcription of cytokines
• There is a reduction in
IkB degradation when
DHA is present
• DHA reduces translocation
of NF-B to nucleus
Effect of DHA on IB & NF-B
Kong W. et al, 2010
24. Kong W. et al, 2010
ELISAAssays show:
• Reduction in IL-12
• Reduction in IL-23
• Reduction in IL-27
• Effect diminishes below 1 M
Effect of DHA on Cytokine Production
25. Lipid Peroxidation
• PUFAs are highly susceptible!
• Free radical attacks the methylene C between
the double bonds in the FA chain
• Increased by presence of O2 and transition
metal ions.
• Autocatalytic
• Considered as one of the few examples of
carbon-centered radical production in cells
26. Membrane lipid peroxidation involves 3 steps
1) Initiation
-by hydrogen extraction by a
radical species
2) Propagation
-O2 rapidly adds on to carbon-
centered radical L, yielding peroxy
radical, LOO
-LOO can then attack nearby
PUFA, creating a chain reaction
3) Termination
- Arrangement into stable products
27. The Good,
• Reactive lipid species may
benefit cell
• Fast & easy way for
membrane to initiated a
nonspecific response to
external stress
The Bad
• Reactive Lipid Species (RLS)
are electrophilic in nature
and capable of reacting with
nucleophilic amino acids
• Thiol groups can act as a redox-
switch controlling cell signaling,
metabolism or gene expression
& the Gooder
RLS-mediated signaling is involved in various physiological
pathways: apoptosis, induction of antioxidative defense,
membrane repair, proteosomal pathways
28. MUFAs have
many of the
benefits of
PUFAs but are
less susceptible
to oxidation
29. PUFA & membrane fission?
• PUFAs make lipid
bilayers more flexible
• Up to 80% of
phospholipids in
exocytotic synaptic
vesicles are
polyunsaturated
• Treatment of neurons
with PUFAs stimulate
SNARE assembly and
the recycling of synaptic
vesicles
• In GUVs, PUFAs
facilitates the enzyme,
dynamin that self-
assembly, involved in
membrane fission
