Coconut oil and the "AA release" - TLR connection
Taka
claim that switching to coconut oil EFAD diet releases arachidonic
acid (AA) and causes transient worsening of systemic inflammation
symptoms before reaching the EFAD state. This also explains why
Mercola.com advertises consuming coconut oil (rich in lauric acid)
together with the anti-inflammatory Omega-3 PUFAs such as DHA/EPA to
prevent the AA-release (means COX-2 expression and the formation of
the inflammatory mediators such as PGE2). It may be better to stay
away from lauric acid (coconut) to prevent systemic inflammation
unless one intends to go EFAD (with Mead acid there is "no COX-2",
AFAIK).
In the papers they claim that SFA (lauric acid) is a component of the
bacterial endotoxin/LPS and therefore stimulates the innate immunity
system via TLRs . This leads to NFkappaB induction and the whole
systemic inflammatory cascade is booted. I wonder whether the longer
chain SFAs present in meat fat and butter do the same?
FASEB J. 2001 Dec;15(14):2556-64.
Modulation of the expression of cyclooxygenase-2 by fatty acids
mediated through toll-like receptor 4-derived signaling pathways.
Hwang D.
Pennington Biomedical Research Center, Louisiana State University,
Baton Rouge, Louisiana 70808, USA. hwangdh[at]pbrc.edu
Genetic evidence that Toll-like receptor 4 (Tlr4) is the
lipopolysaccharide (LPS) receptor and biochemical evidence that Tlr4
confers LPS responsiveness as determined by activation of NF-kappaB
and expression of inducible cyclooxygenase 2 have been demonstrated.
Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are
essential for biological activities of LPS. It is now demonstrated
that SFAs, but not unsaturated fatty acids (UFAs), induce NF-kappaB
activation and expression of COX-2 and other inflammatory markers in
macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS.
Additional evidence suggests that both SFA-induced COX-2 expression
and its inhibition by UFAs are mediated through a common signaling
pathway derived from Tlr4. These results represent a novel mechanism
by which fatty acids modulate signaling pathways and target gene
expression. Whether fatty acids also modulate signaling pathways and
target gene expression derived from the activation of other Tlrs
remains to be determined.-Hwang, D. Modulation of the expression of
cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-
derived signaling pathways.
PMID: 11726530
J Biol Chem. 2004 Apr 23;279(17):16971-9. Epub 2004 Feb 13.
Saturated fatty acid activates but polyunsaturated fatty acid inhibits
Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1.
Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH,
Fitzgerald KA, Hwang DH.
Western Human Nutrition Research Center, The Agricultural Research
Service-United States Department of Agriculture, and Department of
Nutrition, University of California-Davis, Davis, California 95616,
USA.
Toll-like receptor 4 (TLR4) and TLR2 agonists from bacterial origin
require acylated saturated fatty acids in their molecules. Previously,
we reported that TLR4 activation is reciprocally modulated by
saturated and polyunsaturated fatty acids in macrophages. However, it
is not known whether fatty acids can modulate the activation of TLR2
or other TLRs for which respective ligands do not require acylated
fatty acids. A saturated fatty acid, lauric acid, induced NFkappaB
activation when TLR2 was co-transfected with TLR1 or TLR6 in 293T
cells, but not when TLR1, 2, 3, 5, 6, or 9 was transfected
individually. An n-3 polyunsaturated fatty acid (docosahexaenoic acid
(DHA)) suppressed NFkappaB activation and cyclooxygenase-2 expression
induced by the agonist for TLR2, 3, 4, 5, or 9 in a macrophage cell
line (RAW264.7). Because dimerization is considered one of the
potential mechanisms for the activation of TLR2 and TLR4, we
determined whether the fatty acids modulate the dimerization. However,
neither lauric acid nor DHA affected the heterodimerization of TLR2
with TLR6 as well as the homodimerization of TLR4 as determined by co-
immunoprecipitation assays in 293T cells in which these TLRs were
transiently overexpressed. Together, these results demonstrate that
lauric acid activates TLR2 dimers as well as TLR4 for which respective
bacterial agonists require acylated fatty acids, whereas DHA inhibits
the activation of all TLRs tested. Thus, responsiveness of different
cell types and tissues to saturated fatty acids would depend on the
expression of TLR4 or TLR2 with either TLR1 or TLR6. These results
also suggest that inflammatory responses induced by the activation of
TLRs can be differentially modulated by types of dietary fatty acids.
PMID: 14966134
J Biol Chem. 2001 May 18;276(20):16683-9. Epub 2001 Mar 2.
Saturated fatty acids, but not unsaturated fatty acids, induce the
expression of cyclooxygenase-2 mediated through Toll-like receptor 4.
Lee JY, Sohn KH, Rhee SH, Hwang D.
Pennington Biomedical Research Center, Louisiana State University,
Baton Rouge, Louisiana 70808, USA.
Results from our previous studies demonstrated that activation of Toll-
like receptor 4 (Tlr4), the lipopolysaccharide (LPS) receptor, is
sufficient to induce nuclear factor kappaB activation and expression
of inducible cyclooxygenase (COX-2) in macrophages. Saturated fatty
acids (SFAs) acylated in lipid A moiety of LPS are essential for
biological activities of LPS. Thus, we determined whether these fatty
acids modulate LPS-induced signaling pathways and COX-2 expression in
monocyte/macrophage cells (RAW 264.7). Results show that SFAs, but not
unsaturated fatty acids (UFAs), induce nuclear factor kappaB
activation and expression of COX-2 and other inflammatory markers.
This induction is inhibited by a dominant-negative Tlr4. UFAs inhibit
COX-2 expression induced by SFAs, constitutively active Tlr4, or LPS.
However, UFAs fail to inhibit COX-2 expression induced by activation
of signaling components downstream of Tlr4. Together, these results
suggest that both SFA-induced COX-2 expression and its inhibition by
UFAs are mediated through a common signaling pathway derived from
Tlr4. These results represent a novel mechanism by which fatty acids
modulate signaling pathways and target gene expression. Furthermore,
these results suggest a possibility that propensity of monocyte/
macrophage activation is modulated through Tlr4 by different types of
free fatty acids, which in turn can be altered by kinds of dietary fat
consumed.
PMID: 11278967
J Lipid Res. 2003 Mar;44(3):479-86. Epub 2002 Dec 1.
Differential modulation of Toll-like receptors by fatty acids:
preferential inhibition by n-3 polyunsaturated fatty acids.
Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, Hwang
DH.
Pennington Biomedical Research Center, Louisiana State University,
Baton Rouge, LA 70808, USA.
Human subjects consuming fish oil showed a significant suppression of
cyclooxygenase-2 (COX-2) expression in blood monocytes when stimulated
in vitro with lipopolysaccharide (LPS), an agonist for Toll-like
receptor 4 (TLR4). Results with a murine monocytic cell line (RAW
264.7) stably transfected with COX-2 promoter reporter gene also
demonstrated that LPS-induced COX-2 expression was preferentially
inhibited by docosahexaenoic acid (DHA, C22:6n-3) and eicosapentaenoic
acid (EPA, C20:5n-3), the major n-3 polyunsaturated fatty acids
(PUFAs) present in fish oil. Additionally, DHA and EPA significantly
suppressed COX-2 expression induced by a synthetic lipopeptide, a TLR2
agonist. These results correlated with the preferential suppression of
LPS- or lipopeptide-induced NF kappa B activation by DHA and EPA. The
target of inhibition by DHA is TLR itself or its associated molecules,
but not downstream signaling components. In contrast, COX-2 expression
by TLR2 or TRL4 agonist was potentiated by lauric acid, a saturated
fatty acid. These results demonstrate that inhibition of COX-2
expression by n-3 PUFAs is mediated through the modulation of TLR-
mediated signaling pathways. Thus, the beneficial or detrimental
effects of different types of dietary fatty acids on the risk of the
development of many chronic inflammatory diseases may be in part
mediated through the modulation of TLRs.
PMID: 12562875
TLRs: http://en.wikipedia.org/wiki/Toll-like_receptor
Never thought of it this way. Better leave flax oil to painters,
lauric acid to soap makers and stay with the good old MUFA-rich animal
fat ...
Taka
Taka
shampoos) acts like the LPS/endotoxin on TLR4:
J Biol Chem. 2003 Sep 26;278(39):37041-51. Epub 2003 Jul 15.
Reciprocal modulation of Toll-like receptor-4 signaling pathways
involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and
polyunsaturated fatty acids.
Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH.
Western Human Nutrition Research Center, Agricultural Research
Service, United States Department of Agriculture, Davis, California
95616, USA.
Toll-like receptor-4 (TLR4) can be activated by nonbacterial agonists,
including saturated fatty acids. However, downstream signaling
pathways activated by nonbacterial agonists are not known. Thus, we
determined the downstream signaling pathways derived from saturated
fatty acid-induced TLR4 activation. Saturated fatty acid (lauric acid)-
induced NFkappaB activation was inhibited by a dominant-negative
mutant of TLR4, MyD88, IRAK-1, TRAF6, or IkappaBalpha in macrophages
(RAW264.7) and 293T cells transfected with TLR4 and MD2. Lauric acid
induced the transient phosphorylation of AKT. LY294002, dominant-
negative (DN) phosphatidylinositol 3-kinase (PI3K), or AKT(DN)
inhibited NFkappaB activation, p65 transactivation, and
cyclooxygenase-2 (COX-2) expression induced by lauric acid or
constitutively active (CA) TLR4. AKT(DN) blocked MyD88-induced
NFkappaB activation, suggesting that AKT is a MyD88-dependent
downstream signaling component of TLR4. AKT(CA) was sufficient to
induce NFkappaB activation and COX-2 expression. These results
demonstrate that NFkappaB activation and COX-2 expression induced by
lauric acid are at least partly mediated through the TLR4/PI3K/AKT
signaling pathway. In contrast, docosahexaenoic acid (DHA) inhibited
the phosphorylation of AKT induced by lipopolysaccharide or lauric
acid. DHA also suppressed NFkappaB activation induced by TLR4(CA), but
not MyD88(CA) or AKT(CA), suggesting that the molecular targets of DHA
are signaling components upstream of MyD88 and AKT. Together, these
results suggest that saturated and polyunsaturated fatty acids
reciprocally modulate the activation of TLR4 and its downstream
signaling pathways involving MyD88/IRAK/TRAF6 and PI3K/AKT and further
suggest the possibility that TLR4-mediated target gene expression and
cellular responses are also differentially modulated by saturated and
unsaturated fatty acids.
PMID: 12865424
Just makes me wondering, is this why shampoo gives me dandruff?
Taka
MattLB
> This is it, the following papers show the mechanism behind Monty's
> claim that switching to coconut oil EFAD diet releases arachidonic
> acid (AA) and causes transient worsening of systemic inflammation
> symptoms before reaching the EFAD state.
I don't see how you come to this conclusion. The papers are about FA
modulation of membrane-linked signalling cascades and say nothing
about AA release from eating coconut oil. In fact the only AA-related
bit I could see was that AA *doesn't* stimulate COX expression.
"Unlike saturated fatty acids, all unsaturated fatty acids (C18:1n-9,
C18:2n-6, C20:4n-6, C20:5n-3, and C22:6n-3) and conjugated linoleic
acid (cLA) tested were unable to induce COX-2 expression in RAW 264.7
cells"
MattLB
Taka
are not innocent. A quote from the full text: "Our data clearly show
that palmitate and stearic acid, and to a lesser extent lauric acid,
activate TLR4 signaling in muscle and that the capacity of these fatty
acids to induce inflammatory signaling and to reduce insulin signaling
and insulin-mediated glucose metabolism is blunted in muscle with a
loss-of-function or absence of TLR4." Palmitate is present in butter
and is made by the body out of excess carbohydrates (fructose) and
protein.
Diabetes. 2007 Aug;56(8):1986-98. Epub 2007 May 22.
Loss-of-function mutation in Toll-like receptor 4 prevents diet-
induced obesity and insulin resistance.
Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM,
Schenka AA, Araújo EP, Vassallo J, Curi R, Velloso LA, Saad MJ.
Department of Internal Medicine, State University of Campinas,
Campinas, São Paulo, Brazil.
Obesity is associated with insulin resistance and a state of abnormal
inflammatory response. The Toll-like receptor (TLR)4 has an important
role in inflammation and immunity, and its expression has been
reported in most tissues of the body, including the insulin-sensitive
ones. Because it is activated by lipopolysaccharide and saturated
fatty acids, which are inducers of insulin resistance, TLR4 may be a
candidate for participation in the cross-talk between inflammatory and
metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-
of-function mutation in TLR4, are protected against the development of
diet-induced obesity. In addition, these mice demonstrate decreased
adiposity, increased oxygen consumption, a decreased respiratory
exchange ratio, improved insulin sensitivity, and enhanced insulin-
signaling capacity in adipose tissue, muscle, and liver compared with
control mice during high-fat feeding. Moreover, in these tissues,
control mice fed a high-fat diet show an increase in IkappaB kinase
complex and c-Jun NH(2)-terminal kinase activity, which is prevented
in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection
from saturated fatty acid-induced insulin resistance is observed.
Thus, TLR4 appears to be an important mediator of obesity and insulin
resistance and a potential target for the therapy of these highly
prevalent medical conditions.
PMID: 17519423
and here glucose seems to give it another kick by augmenting the LPS/
SFA proinflammatory signaling via NFkappaB:
J Endocrinol. 2008 Jan;196(1):45-55.
High glucose enhances lipopolysaccharide-stimulated CD14 expression in
U937 mononuclear cells by increasing nuclear factor kappaB and AP-1
activities.
Nareika A, Im YB, Game BA, Slate EH, Sanders JJ, London SD, Lopes-
Virella MF, Huang Y.
Division of Endocrinology, Diabetes and Medical Genetics, Department
of Medicine, Medical University of South Carolina, Charleston, South
Carolina 29401, USA.
We have demonstrated recently that high glucose augments
lipopolysaccharide (LPS)-stimulated matrix metalloproteinase (MMP) and
cytokine expression by U937 mononuclear cells and human monocyte-
derived macrophages. Since CD14 is a receptor for LPS, one potential
underlying mechanism is that high glucose enhances CD14 expression. In
the present study, we determined the effect of high glucose on CD14
expression by U937 mononuclear cells. After being chronically exposed
to normal or high glucose for 2 weeks or longer, cells were treated
with LPS for 24 h. Real-time PCR showed that although high glucose by
itself did not increase CD14 expression significantly, it augmented
LPS-stimulated CD14 expression by 15-fold. Immunoassay showed a marked
enhancement of both membrane-associated and soluble CD14 protein
levels by high glucose. Further investigations using transcription
factor activity assays and gel shift assays revealed that high glucose
augmented LPS-stimulated CD14 expression by enhancing transcription
factor nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1)
activities. Finally, studies using anti-CD14 neutralizing antibody
showed that CD14 expression is essential for the enhancement of LPS-
stimulated MMP-1 expression by high glucose. Taken together, this
study has demonstrated a robust augmentation by high glucose of LPS-
stimulated CD14 expression through AP-1 and NFkappaB transcriptional
activity enhancement, elucidating a new mechanism by which
hyperglycemia boosts LPS-elicited gene expression involved in
inflammation and tissue destruction.
PMID: 18180316
But I am wondering what is the evolutionary advantage that saturated
fat induces systemic inflammation??? Is it some kind of autophagy on
a whole organism level to "recycle" its tissues during the summer
feeding months?
Taka
Taka
> On Jan 11, 8:39 am, Taka <taka0...@gmail.com> wrote:
>
> > This is it, the following papers show the mechanism behind Monty's
> > claim that switching to coconut oil EFAD diet releases arachidonic
> > acid (AA) and causes transient worsening of systemic inflammation
> > symptoms before reaching the EFAD state.
>
> I don't see how you come to this conclusion. The papers are about FA
> modulation of membrane-linked signalling cascades and say nothing
> about AA release from eating coconut oil. In fact the only AA-related
> bit I could see was that AA *doesn't* stimulate COX expression.
Well they say that lauric acid (main component of coconut oil, this is
common knowledge) stimulates COX-2. Higher COX-2 means that more of
the AA metabolites like PGE2 are made (given that AA is present in the
cells), right? By the "AA release" I actually mean the appearance of
its proinflammatory metabolites like PGE2, this may be confusing. But
I think Monty talks about temporary symptoms of inflammatory nature
when switching to SFA/coconut oil diet and also explains the confusing
results of many coconut oil feeding experiments in animals by the fact
that the animals have AA in their cells prior to switching to the SFA
diet and that the AA gets released by this diet. So far I did not
understand why there are more AA-related inflammatory symptoms when
switching to coconut oil but these papers make it clear. TLR
signaling is a very powerful mechanism to protect us from bacterial
infections but it's surprising that SFAs can activate it.
If we speak about the AA release literally (from phospholipids), this
is performed by the PLA2 enzymes which seem to be stimulated by
glucose (see my previous post entitled "Glucose induced inflammation -
molecular mechanism?").
> "Unlike saturated fatty acids, all unsaturated fatty acids (C18:1n-9,
> C18:2n-6, C20:4n-6, C20:5n-3, and C22:6n-3) and conjugated linoleic
> acid (cLA) tested were unable to induce COX-2 expression in RAW 264.7
> cells"
Given that more unsaturated fatty acids (n-3) give us more lipid
peroxidation and DHA impairs maximum lifespan, the safest choice for
consumption by the ordinary "AA crowd people" is probably C18:1n9, the
oleic acid (MUFA). This goes well with the latest "heart healthy
MUFAs movement" as well as the Mediterrian diet rich in olive oil
(high oleic + powerful antioxidants). I wouldn't be surprised if the
trans C18:1n9 was even better since it's present in the long-lived
individuals (see the past Monty's post entitled "Trans fat for
longevity").
Taka