Omega-3 fatty acids
what is the only way to attain high levels of EPA and DHA in the blood and/or cell membranes?
attain it through dietary intake
what are the potential routes of lipid oxidation?
auto-oxidation, photo-oxidation, and metal-catalyzed oxidation
Resolvin D1 (RvD1) from?
DHA
conditionally essential fatty acids
EPA and DHA
fish oils contain the omega-3 fatty acids ___ and __
EPA and DHA
EPA and DHA are more susceptible to __ ___ than other fatty acids because they simply have more ___ __ ( __ and __ respectively)
lipid oxidation, double bonds, 5, 6
EPA supplementation reduced __ __ __ by 19%
major coronary events
omega-3s counter the effects of ___
mercury
is there present evidence for greater bioavailability of KO vs FO
no, more carefully controlled human trials must be performed to establish their relative efficacies after chronic administration
a toxic by-product of polyunsaturated fatty acid oxidation
oxidative lipid peroxides
the lipid peroxides generated can promote __ __ that can damage the __ of these prostate cells
oxidative stress, DNA
what directly affects the amount and type of eicosanoids that are produced?
ratio of long-chain omega-6:omega-3 fatty acids
a valid and reliable index of habitual dietary intake of omega-3 fatty acid intake
red blood cell membrane EPA and DHA
signs of inflammation
redness, swelling, heat, and pain
___ ___ in toxic contaminants can make decisions on selecting the type of fish to eat or not eat more difficult
regional variations
hydroperoxides breaks down over time into ___ ___ __ ( __, __, and __ __ __ __) which cause the unpleasant odors associated with ___ ___
secondary oxidation products, aldehydes, ketones, short chain fatty acids, rancid oils
what is the role of resolvins?
the role of resolvins is to shut off the ongoing inflammatory porcess thereby limiting tissue damage
at moderate levels PGE2 supports __ __ but at high concentrations it promotes ___ __
bone formation, bone resorption
Enzyme activities are also elevated such as ___ and ___ ___
catalase, glutathione peroxidase
function of Thromboxane A2
causes vasoconstriction, promotes platelet aggregation
what do farm-raised salmon have high levels of?
dioxins, polychlorinated biphenyls (PCB) and Chlordane
EPA directly stabilizes ___ ___
electrical activity
what kind of salmon have lower concentrations of mercury (farm-raised or wild-ocean caught?)
farm raised
larger omega-3 to toxin ratio
farm-raised salmon
typical western diets provide ratios of omega-6: omega-3 ranging from __:__ to __:__
10:1 to 20:1
when over-the-counter fish oil supplements have been investigated the frequency of excess oxidation is between __ and __% of the products tested
11-62
what should a healthy ratio of omega-6:omega-3 be?
1:1 to 4:1
heart tissue phospholipid DHA proportions are __% vs __% for EPA
2, 0.5
how many g per day of EPA/DHA is required for significant benefit?
3g/day
__% of adults have blood mercury concentrations > 5.8 micrograms/ liter; the EPA's cut off for the dose without an appreciable lifetime risk of harm
4
intermediate risk zone for the omega-3 index
4-7.9%
dietary induced changes in the fatty acid composition of the plasma membrane is largely complete within __ to __ weeks
6, 8
Desirable risk zone for the omega-3 index
8% and above
ALA to DHA in men is ___%
<0.05%
ALA to DHA in women of reproductive age is ___%
<0.1%
how many grams of omega-3 fatty acids is likely to cause fishy aftertaste?
>3g/d
Greenland Eskimos have an average intake of 6g of EPA per day with no known reported ___ disorders
bleeding
RBC membrane EPA and DHA composition positively correlate with __ __, __, ___, ___, __ __, __ and __ __ and ___ __ __
blood plasma, platelet, WBC, adipose, breast milk, skeletal cardiac muscle, brain gray matter
explain how PPAR-gamma acts a tumor suppressor
by activating the gene for syndecan-1 (SDC-1), a proteoglycan which inhibits the phosphorylation and therefore activation of other transcription factors involved in cell division
how does EPA inhibit the release of arachidonic acid from phospholipids?
by competitively inhibiting phospholipase A2
how does EPA reduce eicosanoid production?
by competitively inhibiting the enzymes COX and 5-LOX
how can omega-3s prevent calcium overload?
by inhibiting the activity of L-type Ca2+ channels during periods of stress and increase the activity of cardiac Ca2+/Mg2+ ATPase active transports responsible for moving calcium back into the SR from the cytosol
how does Resolvins E1, Resolvin D2 and Neuroprotectin inhibit neutrophil infiltration at sites of inflammation?
by reducing E-selectin and ICAM-1 expression
the elongase enzymes (Elovl2 and Elovl5) are multi-enzyme complexes similar to fatty acid synthase using a 4 step chain reaction beginning with a ___ reaction using __ - ___
condensation, malonyl-CoA
what acts a risk factor for coronary heart disease?
omega-3 index
delta 5- desaturase is also called?
fatty acid desaturase 1 (FADS1)
delta 6- desaturase is also called?
fatty acid desaturase 2 (FADS2)
MI risk may be reduced by the consumption of?
fish high in PUFAs and low in methylmercury
while a serving of fish may contain anywhere from 10 to 1,000 ppb of mercury, __ ___ ___ have not been found to contain similar mercury levels
fish oil supplements
unsaturated fats are ___ at room temperature
fluid
produced when fish oil oxidizes
hydroperoxides
what are omega-3 fatty acids in fish oil thought to be beneficial in treating?
hypertriglyceridemia, heart disease, insulin resistance, canter, and neurodegenerative disease, depression anxiety, as well as ameliorating inflammatory diseases including rheumatoid arthritis, osteoporosis, inflammatory bowel disease and asthma
What are the 3 conditions for which fish oil and other omega-3 sources are most highly recommended?
hypertriglyceridemia, hypertension, preventing secondary cardiovascular disease
ALA can be found where?
in all tissues
The conversion of ALA to EPA, and DHA occurs where?
in the smooth endoplasmic reticulum except for the final beta-oxidation step which occurs in a peroxisome
the signs of inflammation are a result of what?
increased blood flow and increased permeability across the capillaries, which are driven by metabolites generated from the phospholipid membrane fatty acid arachidonic acid
what does the activation of PPAR-alpha cause?
increases hepatic Beta-oxidation via the activation of lipoprotein lipase leading to the reduction of the fatty acid substrates for triacylglycerol synthesis
part of the body's immediate response to infection or injury
inflammation
could account for the varying degree of effectiveness, and other inconsistencies associated with fish oil supplementation which has been reported in the literature
oxidation products
various markers of oxidative stress and redox balance are affected by __ __
oxidized lipids
which kind of fish needs less membrane fluidity?
tropical fish, increase temperature= increase fluidity
function of Leukotriiene B4
vasoconstriction, bronchospasm, increased vascular permeability
function of PGD2 and PGE2
vasodilation, increased vascular permeability
what happens if both omega-3 and omega-6 fatty acids are present?
they will compete to be transformed into their respective eicosanoids
why are polyunsaturated fatty acids to susceptible to oxidation?
this is because the double bonds between carbons in the polyunsaturated fatty acid are sp^2 hybridized and the p-p pi bond electrons are east to grab and pull away, especially by free radicals who are looking for an extra electron to achieve stability
what do fish oil supplements add as an preservative?
vitamin E
farm-raised salmon can still be safely recommended for both adult men and women, but should be avoided by __ __ and __, and __ women
young children, pregnant, nursing women
PUFAs acutely affect __- __ __ __ fatty acid uptake and increase __ __ __
triacylglycerol-derived skeletal muscle, postprandial insulin sensitivity
EPA and DHA functions: DECREASES: 1. ___ 2. ___ 3. __ 4. __ ___ 5. ___ ___ 6. __ ___ 7. __ __ INCREASES 1. __ ___
triglycerides, inflammation, atherosclerosis, insulin resistance, doxorubicin cardiomyopathy, cardiac fibrosis, oxidative stress, endothelial function
Resolvin E1 (RvE1) from?
EPA
inhibits the release of arachidonic acid from phospholipids
EPA
it has been shown that anti-proliferative action is greater for (EPA/DHA)?
EPA
what do Resolvins E1, Resolvin D2 and Neuroprotectin inhibit?
IL-1 and TNF production and neutrophil infiltrations at the sites of inflammation
free fatty acids will block the phosphorylation of the secondary messengers __ and __ __ leading to reduced __ __ translocation to muscle cell plasma membrane
IRS, PI3 Kinase, GLUT 4
potent stimulator of bone resorption at high concentrations
PGE2
EPA alone has many beneficial effects such as being a stronger activator of ___ - __ which mediated EPAs ____ actions
PPAR-alpha, hypolipidemic
EPA and DHA decrease triacylglycerol concentrations by regulating 2 nuclear transcription factors: 1. activation of ___- __ 2. Decreased activation of __ __ __- __ __ - __ (___- __)
PPAR-alpha, sterol regulatory element-binding protein- 1c (SREBP-1)
transcription factor that serves as a tumor suppressor
PPAR-gamma
EPA and DHA are activators of __- __, which down-regulates the activity of __ which plays a key role in the regulation of gene expression in inflammatory responses by cells
PPAR-gamma, NFkB
EPA and DHA will bind to and activate ___ which inhibits the activation of ___ and hence limiting its inflammatory actions
PPAR-gamma, NFkB
bypass the 1st rate limiting step
Stearidonic acid
compared to ALA, ____ ____ consumption results in a much higher EPA concentration, but not DHA
Stearidonic acid
there is evidence that lipid membrane peroxidation is involved in human disease and it has been established that oxidized lipids can cause ___, ___, and __ ___ leading to ___
inflammation, atherosclerosis, DNA damage, carcinogenesis
Fish do not actually produce omega-3 fatty acids, but instead accumulate them by consuming either ___ or __ __ that have accumulated omega-3 fatty acids
microalgae, prey fish
ALA to EPA biosynthesis is limited at ___%
0.2%
equation for omega-3 index (%)
(erythrocyte EPA+ erythrocyte DHA)/ (erythrocyte total fatty acids)X 100
modulator of osteoblast activity
PGE2
undesirable risk zone for the omega-3 index
0-3.9%
what are 3 reasons behind the lack of positive findings?
1. EPA and DHA used in many studies was probably below the anit-inflammatory threshold 2. possibility of lipid peroxidation of the fish oil supplements provided in various studies 3. common genetic variants of the FADS1 and FADS2 genes may contribute to variable responses to omega-3 supplementation
omega-3 fatty acid benefits on lipids
1. TG decreased 2. RLP decreased
omega-3 fatty acid benefits on plaque stabilization
1. arrhythmias decreased 2. mitochondrial function increased
function of anti-thrombotic
1. decrease platelet aggregation 2. decrease blood viscosity 3. influence clotting factors
function of anti-atherogenic
1. decrease triglycerides 2. inhibit SMC migration/ proliferation 3. affects cytokins/ adhesion molecules
function of anti-arrhythmic
1. favorable mediator profiles 2. influence membrane ion channels 3, increase VF threshold (HRV) 4. alter membrane fluidity 5. limit ischemic damage
function of vasoprotective
1. improve vascular endothelial cell function 2. modulate receptor-agonist interactions 3. reduce blood pressure 4. reduce end organ damage
omega-3 fatty acid benefits on vessels
1. inflammation decreased 2. endothelial function increased 3. vasodilation increased
omega-3 fatty acid benefits on platelets
1. platelet aggregation decreased 2. blood rheology increased
essential fatty acid which plants synthesize
ALA
What is one explanation for the poor conversion of ALA to DHA?
ALA is the most rapidly oxidized unsaturated FA and so a large portion of ingested ALA is beta-oxidaized to acetyl-CoA
should we supplement patients with EPA, DHA, or Both?
Both
which 2 enzymes have a much higher affinity (lower km) for arachidonic acid
COX and LOX
atherosclerosis is an inflammatory disease and EPA is the substrate for __ and __- __ to generate 3-series __ and 5-series ___ that attenuate pro-inflammatory properties compared to their arachidonic derived counterparts
COX, 5-LOX, prostaglandins, leukotrienes
better for reducing triglycerides: EPA or DHA?
DHA
some studies have suggested that __ is more cardioprotective than EPA
DHA
will increase LDL more: EPA or DHA?
DHA
the higher capacity to up-regulate ALA conversion in women may be important for meeting the demands of the fetus and neonate for ___. This may be due to the up-regulatory effects of ____
DHA, estrogen
Note that ___ performed better than ___, which performed better than __
DPA, DHA, EPA
5c,8c,11c, 14c, 17c- 20:5 (20:5n-3)
Eicosapentanoic acid (EPA)
structure with 5 double bonds
Eicosapentanoic acid (EPA)
salmon farmed in ___ have higher PCB concentrations than Salmon farmed in ___, ___, and __ __
Europe, South, Central, North America
what does the FDA recommend about predatory fish?
FDA recommends limiting consumption of predatory fish species due to high levels of toxic contaminant such as mercury
functions of EPA alone: DECREASES: 1. __- __ 2. __ 3. ___
LDL-C, Platelets, triglycerides
what competes with ALA for access to delta 6 desaturase and can limit the production of EPA and DHA, when concentration are too high?
Linoleic acid (LA)
oxidize the p-p pi bond
Lipid carbon-centered radicals
produced when free radicals, such as hydroxyl radicals (the most common culprit)
Lipid-carbon-centered radicals
exposure to methylmercury was associated with increased risk of ___
MI
Omega-3s may inhibit carcinogenesis through: 1. anti-inflammatory (inhibition of ___) 2. pro-apoptotic ( inhibition of __- __) 3. anti-proliferative (inhibition of __, __- __, and other ___) 4. estrogen antagonism (through down-regulation of __ __ or antagonism of __ __ such as __)
NF-kB, Bcl-2, Ras, TGF-beta1, oncogenes, VEGF, estrogen synthesis, estrogen receptors, EGFR
both EPA and DHA down-regulate the activation of ___
NFkB
When is NFkB first activated?
NFkB is first activated by extracellular inflammatory stimuli, and then it translocates to the nucleus to activate the promoter regions of many other pro-inflammatory genes
what are the 2 transcription factors that play a role in inflammation?
Nuclear factor k B (NFkB) and Perioxisome proliferator activated receptor- gamma (PPAR-gamma)
EPA or DHA will compete and replace __ __ at the __- __ position of the ___
arachidonic acid, sn-2 position, glycerophospholipids
PGE2 directly activates the ___ receptor of progenitor osteoclasts which results in their activation
RANKL
the cardiac FA content can be determined by estimating the __ __ FA content
RBC membrane
the ___ fatty acid composition is less variable than ___
RBC, plasma
what are produced through COX-2 and 5-LOX enzymes?
Resolvin E1 (RvE1), Resolvin D1 (RvD1), Neuroprotectin D1 (NPD1)
EPA and DHA also produce novel anti-inflammatory and inflammation resolving mediators called ____
Resolvins
Moderate consistent evidence suggests that increased seafood consumption outweighs the risks associated with ____. However, guidelines advise eating seafood found to be low in mercury (___)
SMASHT
Omega-3 FA's in white adipose tissue activate PPAR-gamma which transcriptionally activates the gene for the ____ ___
adipokine adiponectine
through the activation of PPAR-alpha will reduce skeletal muscle uptake of triacyglycerol as well as inhibit triacyglycerol synthesis pathways and increase free fatty acid Beta-oxidation
adiponectine
delta 6 desaturase activity decreases with __ and after ___ DHA cannot be synthesized from EPA to any appreciable extent
age, infancy
inhbits delta 6 and delta 5 desaturase and reduces EPA and DHA concentrations
alcohol
which one of these omega-3 forms is best absorbed? Omega-3-triglyceride, omega-3 phospholipid, omega-3 ethyl ester?
all the same to enzymes
9c, 12c, 15c-18:3 (18:2n-3)
alpha-linolenic acid (ALA)
structure with 3 double bonds
alpha-linolenic acid (ALA)
how can omega-3's influence cellular ion channels?
altering the electrophysilogy of excitable membranes and therefore directly influence cardiac rhythm and vascular tone and may prevent arrhythmias
Eicosanoids made from omega-3 fatty acids are often referred to as ___- ___
anti-inflammatory ( they are just less inflammatory than those made from omega-6 fats by an order of 10 to 100 fold less potent)
incorporation of Omega-3s into mitochondrial membranes increases oxidative stress which induces ___
apoptosis
with low omega-3 intakes cellular membranes become enriched with an excess of what?
arachidonic acid which is a substrate for PGE2
increased amounts of dietary fish oil results in a decrease in the amount of __ __ in the membranes of cells, with the result being less substrate available for the synthesis of ___ from __ __
arachidonic acid, eicosanoids, arachidonic acid
Refer to question 143 and 144: both of these mechanisms prevent excess Ca2+ from accumulating in the cardiac cell's cytoplasm and may therefore prevent the development of ____
arrhythmias
an inflammatory disease
atherosclerosis
functions of DHA alone: DECREASES: 1. ___ 2. ___ __ 3. __ __ 4. __ INCREASES: 1. __ __ 2. __- __ and __- __ 3. ___
autoantibodies, blood pressure, heart rate, triglycerides, vascular function, HDL-C, LDL-C, lifespan
PCB, dioxin, and chlordane are suspected ___
carcinogens
function of prostcyclin
causes vasodilation, inhibits platelet aggregation
which fish have the most widely available dietary source of EPA and DHA?
cold water oily fish, such as salmon, mackerel, anchovies, sardines, herring, and tuna (SMASHT)
neurotoxic and it also can impair normal neurological development in a fetus or child
methylmercury
increased adiponectin leads to...
decreased hepatic steatosis, insulin resistance, and dyslipidemia
what does decreased activation of SREBP-1 cause?
decreases lipogenesis via reduced production of Fatty acid synthase
linoleic acid to alpha-linolenic acid via ____- ____
delta 15-desaturase (plants only)
what is the rate limiting step in ALA conversion to EPA and DHA?
delta 6 desaturase
1. Linoleic acid (C18:2n-6) a. ___ - ___ 2. gamma-Linolenic acid (C18:3n-6) b.___ 3. di-homo-gamma-Linolenic acid (C20:3n-6) c. __- ___ 4. ARACHIDONIC ACID (C20:4n-6)
delta6-desaturase, elongase, delta5-desaturase
1. alpha-linolenic acid a. ___- ___ 2. Stearidonic aci b.___ 3. (C20:4n-3) c. __- ____ 4. EPA d. ____ 5. Docosapentaenoic acid (C22: 5n-3) e. ___ 6. (C24:5n-3) f. __ - ____ 7. (C24: 6n-3) g. __- ___ 8. DHA
delta6-desaturase, elongase, delta5-desaturase, elongase, elongase, delta6-desaturase, Beta-oxidation
A high dietary ratio of omega-6/omega-3 is positively correlated with what?
depressed bone formation rates and bone mineral density
4c, 7c, 10c, 13c, 16c, 19c -22:6 (22:6n-3)
docosahexaenoic acid (DHA)
structure with 6 double bonds
docosahexaenoic acid (DHA)
DHA induces greater ___ expression in vascular endothelial cells compared to EPA, and therefore DHA is better at increasing vascular function and reducing blood pressure
eNOS
greenland eskimos whose diet is rich in marine derived fish showed lower prevalence of ____ and lower incidences of related diseases such as __ __ __, __ __ __, __, __, __ __ , __ __ __ __, and __ __
inflammation, coronary heart disease, inflammatory bowel disease, psoriasis, asthma, rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis
EPA concentration in all the tissues is very ___
low
plasma and urinary increases in ____ (__), ___, __- ____ and reductions in __ ___ of ___ ___ and ___ have been seen.
malondialdehyde, MDA, oxLDL, 8-oxoGuanine, plasma levels, vitamin C, E
n-3 Fatty acids are positively associated with what?
peak bone mineral density and bone accrual in healthy men
oily fish contains other bioactive compounds ( ___, __, and __) not found in fish oil supplements
peptides, vitamins, minerals
in addition of their role as major substrates for phospholipid membrane structure, cellular energy production, and adipose storage, omgea-3s are also involved in the modulation of ___ functional properties at the cellular level
pleiotrophic
it is also possible for omega-3s to act __- ___ by favoring excess Ca2+ release and triggering ___
pro-arrhythmic, arrhythmias
EPA and DHA are also precursors to the anti-inflammatory ___ and __- __
resolvins, neuroprotectin-D1
DHA concentrations are highest in the ___ and ___ ___
retina, cerebral cortex
DHA supplementation raises EPA levels through ___ - ___
retro-conversion
confounds efforts to establish cause and effect relationships between dietary EPA and DHA
retro-conversion
highest ratio, more omega 3s
salmon
Fatty predatory fish like ___, ___, __, and ___ ___ may be high in omega-3 fatty acids, but due to their position at the top of the food chain, these species may also accumulate toxic substances through biomagnification
sharks, swordfish, tilefish, albacore tuna
why are fish supplements low in mercury? 1. ____ fish are typically used in making fish oil supplements and they tend to be lower on the food chain and contain less mercury 2. mercury binds to ___ (fish meat) 3. Mercury may be reduced or removed during the ___ of fish oil (most fish oils are ___)
smaller, protein, processing, distilled
saturated fats are ____ at room temperature
solid
what can you do to prevent fish burps?
supplements should be taken with meals in equally divided doses throughout the day. Some pills are enteric-coated to help prevent these side effects.
