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.