On Wed, 23 Aug 2000, Amadeus Schmidt wrote:

> >Anti-thrombotic effects of omega-3 (n-3) fatty acids are believed
> >to be due to their ability to reduce arachidonic acid levels.
>
> I thought we are attributing the main health advantages of essential FA
> oils to their effect on prostaglandin formation.
> PG-1 have the most positive effects (particularly PGE1),
> PG-2 have the deteriorating effects (in excess)
> PG-3 are down-modulating PG-2 effects.

That's about right.  It's not really true that PG1 is "good" and
PG2 is "bad," but rather that typical Western diets cause us to
make too much PG2.

> As PG-2 are made of AA and PG-3 out of w-3 LNA and EPA.
> So the goal should be at first to boost PG-1 and then
> to downregulate PG-2 by whatever. In this order.
> Not only to reduce AA levels.
> AA is not only formed, it is also eaten.

GLA and DGLA are also eaten.  GLA is found in chicken fat, for
example (This is probably why chicken soup is good for people
with fevers), and DGLA is in liver and other organ meats.  When
AA is eaten, it has little effect on PG2 production because it is
taken up by red blood cells, which lack cyclooxygenase, the
enzyme needed to convert AA to PG2.

> >... The effect of diet on the
> >rate-limiting enzyme of arachidonic acid biosynthesis (delta
> >6-desaturase) and on the lipid composition of hepatic microsomal
> >membrane was determined. Both linseed oil- or fish oil-containing
> >diets inhibited conversion of linoleic acid to gamma-linolenic
> >acid.
>
> Why should we want *this*? GLA is the precursor for all the good PG-1's.
> Inhibiting this step would rob away the positive PG-1 at first....
> D6d inhibition indeed is a major problem, because trans-fats,
> alcohol and some more substances inhibit d6d, disabling *all*
> EFA aktivity. We should *want* d6d activity. On EFAs w-3 and w-6.

Well, it's the w-3 EFAs that are doing the inhibiting.  According
to Sears, we expect ALA, but not EPA/DHA to inhibit PG1 (and PG2)
synthesis.  Garg's experiments indicate that it is not so simple.

> >Inhibition was greater with fish oil than with linseed oil,
> >only when fed with saturated fat.
>
> Makes sense, that SFA does this, because SFA and linseed both compete for
> D6D. But "greater"?  SFA  *alone* can inhibit d6d activity on EFAs.
> I can't see why fish oil (containing end product EFA) should influence D6D
> rate (it influences PG-2 formation out of AA).

Right.  This suggests that there is something wrong with the
theory.  Perhaps there are more feedback mechanisms than we
currently understand.  Even Sears has had to withdraw his
negative claims about dietary ALA.  Although they *should*
inhibit PG1 production, there is no good evidence that they do.
We seem to have a similar situation with respect to SFAs.

> However the advantage of w-3 only against w-3 with SFA would be that
> 1. it is made to EPA, which downregulates PG-2 (bad) making out of AA.
> 2. it is made to DHA - for the nerves.

Is there any evidence that SFA interferes with these processes?

> >These observations indicate that the efficacy of n-3 fatty acids
> >in reducing arachidonic acid level is dependent on the linoleic
> >acid to saturated fatty acid ratio of the diet consumed.
>
> We want more PG-1 out of DGLA and less PG-2 out of AA.
> But DGLA is only one step away from AA and both are w-6 series.
> So we'd want to promote prostaglandin(-1) formation of DGLA and
> downregulate PG-2 formation out of AA.
> The latter is done by EPA, which comes from w-3 LNA.

Or, better, we eat the EPA/DHA directly.

> We also might want to limit the conversion of DGLA to AA.
> But the same enzyme is making EPA too, so we shouldn't want to limit *this*.

Right.  We want to inhibit the conversion of AA to PG2, by
cyclooxygenase.

> What spoke against the SFAs was different:
> As SFAs (only long chain 18 and 16:0) compete at all formation levels
> against EFA activity, the point was that *all* EFA activity is diminished.

Incidentally, it turns out that these two long-chain SFAs
(palmitate and stearate) are the preferred fuel of the heart,
rather than the short-chain ones that you suggested.  This may
have some bearing on the EFA question.  If the long-chain SFAs
are preferentially used for fuel, then they are less in
competition with EFAs for desaturation.

> The point against beef fat was
> 1. To much saturated fat compared to very few total EFAs
> 2. only then: too few w-3 in relation to w-6 EFAs.

Well, I agree with point 2, especially with respect to the
complete lack of EPA/DHA.  I'm not so concerned about the ratio
of SFA to EFA (about 6:1 in tallow).  If the diet is eucaloric,
almost all that SFA will be used as fuel.  The absolute amounts
needed for membranes is small, and there is no clinical evidence
that the SFAs are causing prostaglandin imbalance.

Todd Moody
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