Arachidonic Acid - the secret killer

Arachidonic Acid - the secret killer

For those who like it in pictures:

http :// www .biol.sc.edu/~bergerlab/guest%20lectures%20610/DIXON.ppt

Re: Arachidonic Acid - the secret killer

I had trouble opening it. Can it be accessed another way?

With regard to AA, it basically makes the body biochemically unstable
(assuming that it is in your cells, rather than the natural Mead
acid), so that minor stresses can cause tremendous damage over the
long run, particularly as "chronic inflammation." Many have asked me
about the AA in products like meat, but that seems to be a minor
issue, relative to a diet rich in PUFAs and cooked meat (due to HCAs
and other dangerous molecules generated - most of the small amounts of
AA in meat probably don't get very far, because they are changed
during cooking, etc.), and low in antioxidant-rich food items.

Re: Arachidonic Acid - the secret killer

On Apr 28, 11:06 am, monty1...@lycos,com wrote:
> I had trouble opening it. Can it be accessed another way?

You need MS PowerPoint or a free viewer or compatible suite such as
the OpenOffice (free from SUN) to open it. Some viewers are e.g.:

http :// support.microsoft,com /kb/126492
http :// pptfaq,com /FAQ00153.htm
http :// www .download,com /PowerPoint-Viewer-2007/3000-9694 4-10742145.html

Re: Arachidonic Acid - the secret killer

Taka or Monty, I would be interested in your interpretation of below
abstract:

Comparison of low fat and low carbohydrate diets on circulating fatty
acid composition and markers of inflammation.

Abnormal distribution of plasma fatty acids and increased inflammation
are prominent features of metabolic syndrome. We tested whether these
components of metabolic syndrome, like dyslipidemia and glycemia, are
responsive to carbohydrate restriction. Overweight men and women with
atherogenic dyslipidemia consumed ad libitum diets very low in
carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in
fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In
comparison to the LFD, the VLCKD resulted in an increased proportion
of serum total n-6 PUFA, mainly attributed to a marked increase in
arachidonate (20:4n-6), while its biosynthetic metabolic intermediates
were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid
ratio also increased sharply. Total saturated fatty acids and 16:1n-7
were consistently decreased following the VLCKD. Both diets
significantly decreased the concentration of several serum
inflammatory markers, but there was an overall greater anti-
inflammatory effect associated with the VLCKD, as evidenced by greater
decreases in TNF-alpha, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and
PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3
are commonly viewed as pro-inflammatory, but unexpectedly were
consistently inversely associated with responses in inflammatory
proteins. In summary, a very low carbohydrate diet resulted in
profound alterations in fatty acid composition and reduced
inflammation compared to a low fat diet. PMID: 18046594

-- deleted messages --

-- deleted messages --

Re: Arachidonic Acid - the secret killer

On Jun 12, 1:12 pm, Marshall Price <d0213...@yahoo,com > wrote:
> But most cells can't live without mitochondria, right? So you're
> saying the cells die on a low-carb diet?

Yes, cells with defective or downregulated mitochondria cannot
reproduce well without sugar because they use its glycolysis (under
anaerobic conditions) to produce energy. Normal stem cells could be
such an example but they seem to survive by entering a quiescent state
and using the little glucose body provides even if you don't ingest
any carbohydrates (liver actually makes sugar from protein by
gluconeogenesis). But the malignant cells won't cease dividing easily
and overproduce ROS instead of preserving energy what is going to kill
them first under severe sugar deprivation conditions and Omega-3s can
facilitate this process by triggering apoptosis.

> Including fat and muscle
> cells? That makes no sense to me. Once gone, they're gone for good.

Terminally differentiated cells easily switch their mitochondria from
burning sugar to burning fat if the former is unavailable. The
efficiency of burning fat is lower so the cells additionally amplify
their mitochondria to compensate for this. If they have defective
mitochondria like cancer cells and amplify them they also amplify the
production of ROS what kills them. There are no cells without
mitochondria and the brain or muscle cells contain them in large
numbers. Stem cells like the muscle satellite cells function like a
healthy mitochondria storage and they are injecting them into the
muscle fibers when needed. Also there is a wonderful process of
healthy mitochondria selection/injection during the oocyte
development. Defective mitochondria can be removed by the process of
autophagy which some people here like DZ are trying to accomplish by
intermittent fasting.

Taka

Re: Arachidonic Acid - the secret killer

On Jun 12, 4:34 pm, Taka <taka0...@gmail,com > wrote:
> On Jun 12, 1:12 pm, Marshall Price <d0213...@yahoo,com > wrote:
>
> > But most cells can't live without mitochondria, right? So you're
> > saying the cells die on a low-carb diet?
>
> Yes, cells with defective or downregulated mitochondria cannot
> reproduce well without sugar because they use its glycolysis (under
> anaerobic conditions) to produce energy. Normal stem cells could be
> such an example but they seem to survive by entering a quiescent state
> and using the little glucose body provides even if you don't ingest
> any carbohydrates (liver actually makes sugar from protein by
> gluconeogenesis). But the malignant cells won't cease dividing easily
> and overproduce ROS instead of preserving energy what is going to kill
> them first under severe sugar deprivation conditions and Omega-3s can
> facilitate this process by triggering apoptosis.

Malignant cells dying via apoptosis is a good thing.

> > Including fat and muscle
> > cells? That makes no sense to me. Once gone, they're gone for good.
>
> Terminally differentiated cells easily switch their mitochondria from
> burning sugar to burning fat if the former is unavailable.

There is no switch. Whether burning fat or glucose it's all in the
form of Acetyl CoA by the time the mitochondrion gets going on it.

> The efficiency of burning fat is lower

In what way? The energy output per molecule is much higher than
glucose.

> There are no cells without mitochondria

Red blood cells have no mitochondria.

MattLB

Re: Arachidonic Acid - the secret killer

On Jun 13, 9:39 pm, MattLB <mat...@angelfire,com > wrote:
> There is no switch. Whether burning fat or glucose it's all in the
> form of Acetyl CoA by the time the mitochondrion gets going on it.
>
> > The efficiency of burning fat is lower
>
> In what way? The energy output per molecule is much higher than
> glucose.

Perhaps depending on the chain length ... Energy (ATP) can be
produced from glucose anaerobically, i.e. without oxygen what means
without mitochondria. This is impossible with fatty acids so the
energy production from fat is more "mitochondria costly" and requires
complicated biochemistry (membrane bound enzymatic systems). You need
highly differentiated cells at least in terms of mitochondria to
efficiently produce energy from fat, these are not the malignant cells
which went back to the embryonic state in a sense.

> > There are no cells without mitochondria
>
> Red blood cells have no mitochondria.

You caught me, but I would not consider these true cells because they
have no nuclear DNA/chromosomes either and cannot reproduce (at least
in primates).

Taka

Re: Arachidonic Acid - the secret killer

Taka wrote:
> On Jun 13, 9:39 pm, MattLB <mat...@angelfire,com > wrote:
>> There is no switch. Whether burning fat or glucose it's all in the
>> form of Acetyl CoA by the time the mitochondrion gets going on it.
>>
>>> The efficiency of burning fat is lower
>> In what way? The energy output per molecule is much higher than
>> glucose.
>
> Perhaps depending on the chain length ... Energy (ATP) can be
> produced from glucose anaerobically, i.e. without oxygen what means
> without mitochondria. This is impossible with fatty acids so the
> energy production from fat is more "mitochondria costly" and requires
> complicated biochemistry (membrane bound enzymatic systems). You need
> highly differentiated cells at least in terms of mitochondria to
> efficiently produce energy from fat, these are not the malignant cells
> which went back to the embryonic state in a sense.
>
>>> There are no cells without mitochondria
>> Red blood cells have no mitochondria.
>
> You caught me, but I would not consider these true cells because they
> have no nuclear DNA/chromosomes either and cannot reproduce (at least
> in primates).

Of course they're true cells, and the fact that they don't reproduce
is nothing unusual. Most cells don't reproduce.

I think you've got to review the Cori cycle to understand how
anaerobic metabolism in muscle and red blood cells relies on the
*liver's* ability to oxidize lactate into pyruvate, and look more
closely into how cancer interferes with apoptosis. Here's a passage
from /MBOC4/ p1010 on how important and normal apoptosis is:

-----
Programmed cell death (apoptosis)

The cells of a multicellular organism are members of a highly organized
community. The number of cells in this community is tightly regulated -
not simply by controlling the rate of cell division, but also by
controlling the rate of cell death. If cells are no longer needed, they
commit suicide by activating an intracellular death program. This
process is therefore called *programmed cell death,* although it is more
commonly called *apoptosis* (from a Greek word meaning "falling off," as
leaves from a tree).

The amount of apoptosis that occurs in developing and adult animal
tissues can be astonishing. In the developing vertebrate nervous system,
for example, up to half or more of the nerve cells normally die soon
after they are formed. In a healthy adult human, billions of cells die
in the bone marrow and intestine every hour. It seems remarkably
wasteful for so many cells to die, especially as the vast majority are
perfectly healthy at the time they kill themselves. What purposes does
this massive cell death serve?

In some cases, the answers are clear. Mouse paws, for example, are
sculpted by cell death during embryonic development: they start out as
spadelike structures, and the individual digits separate only as the
cells between them die (Figure 17-35). In many other cases, cell death
helps regulate cell numbers. In the developing nervous system, for
example, cell death adjusts the number of nerve cells to match the
number of target cells that require innervation. In all these cases, the
cells die by apoptosis.

In adult tissues, cell death exactly balances cell division. If this
were not so, the tissue would grow or shrink. If part of the liver is
removed in an adult rat, for example, liver cell proliferation increases
to make up for the loss. Conversely, if a rat is treated with the drug
phenobarbital - which stimulates liver cell division (and thereby liver
enlargement) - and then the phenobarbital treatment is stopped,
apoptosis in the liver greatly increases until the liver has returned to
its original size, usually within a week or so. Thus, the liver is kept
at a constant size through the regulation of both the cell death and the
cell birth rate.

...

The intracellular machinery responsible for apoptosis seems to be
similar in all animal cells. This machinery depends on a family of
proteases that have a cysteine at their active site and cleave their
target proteins at specific aspartic acids. They are therefore called
*caspases.* Caspases are synthesized in the cell as inactive precursors,
or /procaspases,/ which are usually activated by cleavage at aspartic
acids by other caspases (Figure 17-38A). Once activated, caspases
cleave, and thereby activate other procaspases, resulting in an
amplifying proteolytic cascade (Figure 17-38B). Some of the activated
caspases then cleave other key proteins in the cell. Some cleave the
nuclear lamins, for example, causing the irreversible breakdown of the
nuclear lamina; another cleaves a protein that normally holds a
DNA-degrading enzyme (a DNAse) in an inactive form, freeing the DNAse to
cut up the DNA in the cell nucleus. In this way, the cell dismantles
itself quickly and neatly, and its corpse is rapidly taken up and
digested by another cell.

Activation of the intracellular death pathway, like entry into a new
stage of the cell cycle, is usually triggered in a complete, all-or-none
fashion. The protease cascade is not only destructive and
self-amplifying but also irreversible, so that once a cell reaches a
critical point along the path to destruction, it cannot turn back.

...

In the best understood pathway, mitochondria are induced to release the
electron carrier protein /cytochrome c/ (see Figure 14-26) into the
cytosol, where it binds and activates an adaptor protein called *Apaf-1*
(Figure 17-39B). This mitochondrial pathway of procaspase activation is
recruited in most forms of apoptosis to initiate or to accelerate and
amplify the caspase cascade. DNA damage, for example, as discussed
earlier, can trigger apoptosis. This response usually requires p53,
which can activate the transcription of genes that encode proteins that
promote the release of cytochrome /c/ from mitochondria. These proteins
belong to the Bcl-2 family.
-----

So it's no coincidence that cancerous cells' mitochondria aren't
"healthy." Cancer thrives by interfering with mechanisms in the
mitochondrion which ordinarily would cause the orderly death and
disintegration of the cell, *but* it does so without interfering with
those cell functions it needs to survive and grow.

--
Marshall Price of Miami
Known to Yahoo as d021317c

Re: Arachidonic Acid - the secret killer

Taka and Monty: Could you comment on below abstract?

An arachidonic acid-enriched diet does not result in more colonic
inflammation as compared with fish oil- or oleic acid-enriched diets
in mice with experimental colitis.

Fish oils (FO) - rich in EPA and DHA - may protect against colitis
development. Moreover, inflammatory bowel disease patients have
elevated colonic arachidonic acid (AA) proportions. So far, effects of
dietary AA v. FO on colitis have never been examined. We therefore
designed three isoenergetic diets, which were fed to mice for 6 weeks
preceding and during 7 d dextran sodium sulfate colitis induction. The
control diet was rich in oleic acid (OA). For the other two diets, 1.0
% (w/w) OA was exchanged for EPA+DHA (FO group) or AA. At 7 d after
colitis induction, the AA group had gained weight (0.46 (sem 0.54) g),
whereas the FO and OA groups had lost weight ( - 0.98 (sem 0.81) g and
- 0.79 (sem 1.05) g, respectively; P < 0.01 v. AA). The AA group had
less diarrhoea than the FO and OA groups (P < 0.05). Weight and length
of the colon, histological scores and cytokine concentrations in colon
homogenates showed no differences. Myeloperoxidase concentrations in
plasma and polymorphonuclear cell infiltration in colon were decreased
in the FO group as compared with the OA group. We conclude that in
this mice model an AA-enriched diet increased colonic AA content, but
did not result in more colonic inflammation as compared with FO- and
OA-enriched diets. As we only examined effects after 7 d and because
the time point for evaluating effects seems to be important, the
present results should be regarded as preliminary. Future studies
should further elucidate differential effects of fatty acids on
colitis development in time. PMID: 18205994

-- deleted messages --

-- deleted messages --

Re: Arachidonic Acid - the secret killer

Taka or Monty, please comment on below abstract which seems to say
that the amount of dietary LA from 2.5 to 17.5% of energy had little
affect on the amount of AA in neutrophil and plasma lipids, but was
decreased by 4g of fish oil.

Simple relationships exist between dietary linoleate and the n-6 fatty
acids of human neutrophils and plasma.

Eicosanoids, the enzymatically oxygenated products of arachidonic acid
(AA), appear to be overproduced in some disorders of inflammation.
Dietary strategies for decreasing tissue AA require information on the
relationships between dietary linoleic acid (LA) and tissue
concentrations of AA. The use of either high- or low-LA spreads and
cooking oils by healthy male volunteers resulted in a range of LA
intakes of 2.5-17.5% of energy, as estimated by diet-diary analysis.
Analysis of LA and AA concentrations in neutrophils and plasma lipid
fractions from these subjects indicated that there were positive
linear relationships between dietary LA and the LA concentrations in
neutrophil phospholipids, plasma triglycerides, and plasma cholesteryl
esters. By contrast, differences in dietary LA within a broad range
were not associated with differences in concentrations of AA in these
same neutrophil and plasma fractions. AA concentrations were decreased
by supplementation of the diet with 4 g fish oil (1.6 g
eicosapentaenoic acid, 0.3 g docosahexaenoic acid). The results
suggest that the LA content of tissue lipids may be used to estimate
LA intake, and the reduction of dietary LA by using standard dietary
strategies is not likely to lead to reduction in tissue AA whereas
this can be accomplished by fish-oil supplementation. PMID: 8379505

Re: Arachidonic Acid - the secret killer

Arachidonic acid supplementation dose-dependently reverses the effects
of a butter-enriched diet in rats.

Male Sprague Dawley rats were fed a butter-enriched diet (50% fat) for
2 weeks which was supplemented orally with 9, 18, 36, or 72 mg/day of
ethyl arachidonate for a further 2 weeks. The control group of animals
were fed a 5% fat diet for 4 weeks. Aortic prostacyclin (PGI2)
production, platelet aggregation and thromboxane A2 (TXA2) production
and plasma and aortic phospholipid (PL) fatty acids were measured. 50%
butter-feeding resulted in a significant reduction in aortic PGI2
production and collagen-induced platelet aggregation and TXA2
production. These changes were accompanied by a reduction in plasma
and aortic PL arachidonic acid levels and an increase in
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), 5,8,11-
eicosatrienoic acid (ETA) and dihomo-gamma-linolenic acid (DGLA).
These changes in prostanoid production, platelet aggregation and PL
fatty acid composition were dose-dependently reversed by the daily
oral administration of ethyl arachidonate (9, 18, 36, or 72 mg). The
threshold dose being as little as 9 mg of ethyl arachidonate/rat/day
for reversal of PL fatty acid composition, collagen-induced platelet
aggregation and TXA2 production, and 18 mg of ethyl arachidonate/rat/
day for reversal of aortic PGI2 production. Full reversal was seen
generally with 36 or 72 mg of ethyl arachidonate/rat/day. The data
highlight the responsiveness of tissue eicosanoid production to small
quantities (ppm) of dietary eicosanoid precursors. PMID: 8469684