The Molecular Mechanisms Underlying the Pro-Inflammatory Actions of Thiazolidinediones (TZDs) in Human Macrophages
MarilynMann
Thiazolidinediones (TZDs) in Human Macrophages
Julie M. Hall and Donald P. McDonnell*
This version published online on May 8, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0060
It is hypothesized that the anti-inflammatory actions of peroxisome
proliferator-activated receptors (PPARs) may explain the protective
effect of these receptors in diabetes, atherosclerosis, cancer and
other inflammatory diseases. However, emerging evidence for pro-
inflammatory activities of activated PPARs is concerning in light of
new studies which associate PPAR modulators with an increased
incidence of both cardiovascular events in humans and the sporadic
formation of tumors in rodents. In an attempt to define the role of
each PPAR subtype in inflammation, we made the unexpected observation
that human PPAR is a positive regulator of inflammatory responses in
both monocytes and macrophages. Notably, TNF -stimulated cells
administered PPAR agonists express and secrete elevated levels of
inflammatory cytokines. Most surprising, however, was the finding that
thiazolidinediones (TZDs) and other known PPAR ligands display
different degrees of pro-inflammatory activities in a PPAR - and PPAR -
independent manner via their ability to augment PPAR signaling. A
series of mechanistic studies revealed that TZDs, at clinically
relevant concentrations, bind and activate the transcriptional
activity of PPAR. Collectively, these studies suggest that the
observed pro-inflammatory and potentially deleterious effects of PPAR
ligands may be mediated through an off-target effect on PPAR. These
studies highlight the need for PPAR modulators with increased receptor
subtype-specificity. Furthermore, they suggest that differences in
systemic exposure and consequently in the activation of PPAR and PPAR
may explain why TZDs can exhibit both inflammatory and anti-
inflammatory activities in humans.
* * *
In light of the controversy about Avandia, I thought some people might
be interested in this.
Marilyn
Andrew B. Chung, MD/PhD
This underscores the importance of losing the visceral adipose tissue
(VAT) which is a major source of inflammatory cytokines even in the
absence of TZDs.
Vascular Endothelial Growth Factor Is Induced by the Inflammatory
Cytokines Interleukin-6 and Oncostatin M in Human Adipose Tissue In
Vitro and in Murine Adipose Tissue In Vivo.
Arterioscler Thromb Vasc Biol. 2007 May 24;
OBJECTIVE: It is believed that adipose tissue acts as an endocrine
organ by producing inflammatory mediators and thereby contributes to
the increased cardiovascular risk seen in obesity. A link between
adipose tissue mass and angiogenesis has been suggested. Vascular
endothelial growth factor (VEGF) seems to be implicated in this
process. Members of the glycoprotein (gp)130 ligand family regulate
VEGF expression in other cells. METHODS AND RESULTS: We used tissue
explants as well as primary cultures of preadipocytes and adipocytes
from human subcutaneous and visceral adipose tissue to investigate
whether the gp130 ligands oncostatin M (OSM), interleukin-6 (IL-6),
leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1) regulate
VEGF expression in human adipose tissue. Human subcutaneous and
visceral adipose tissue responded to treatment with IL-6 and OSM with
a significant increase in VEGF production. Human preadipocytes were
isolated from subcutaneous and visceral adipose tissue. Adipocyte-
differentiation was induced by hormone-supplementation. All cell types
responded to IL-6 and OSM with a robust increase in VEGF protein
production and a similar increase in VEGF-specific mRNA. Furthermore,
IL-1beta synergistically enhanced the effect of OSM on VEGF
production. AG-490, a JAK/STAT inhibitor, abolished the OSM-dependent
VEGF induction almost completely. In mice, IL-6 and OSM increased
serum levels of VEGF and VEGF mRNA and vessel density in adipose
tissue. CONCLUSIONS: We speculate that the inflammatory cytokines IL-6
and OSM might support angiogenesis during adipose tissue growth by
upregulating VEGF.
May GOD bless you in HIS mighty way making you hungrier than ever.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://ABChung.LiveJournal.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
http://HeartMDPhD.com/Love/TheTruth
MarilynMann
Macrophages From Subjects With Low Plasma HDL-Cholesterol
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1115.)
Lea Sarov-Blat; Robert S. Kiss; Bassam Haidar; Nihan Kavaslar; Michael
Jaye; Melissa Bertiaux; Klaudia Steplewski; Mark R. Hurle; Dennis
Sprecher; Ruth McPherson; Yves L. Marcel
Objective- Reduced plasma concentrations of high-density lipoprotein-
cholesterol (HDL-C) are a significant risk factor for cardiovascular
disease. Mechanisms that regulate HDL-C concentrations represent an
important area of investigation.
Methods and Results- Comparative transcriptome analyses of monocyte-
derived macrophages (MDM) from a large population of low HDL-C
subjects and age- and sex-matched controls revealed a cluster of
inflammatory genes highly expressed in low HDL-C subjects. The
expression levels of peroxisome proliferator activated receptor
(PPAR) and several antioxidant metallothionein genes were decreased
in MDM from all low HDL-C groups compared with controls, as was the
expression of other genes regulated by PPAR, including CD36, adipocyte
fatty acid binding protein (FABP4), and adipophilin (ADFP). In
contrast, PPAR expression was increased in MDM from low HDL-C groups.
Quantitative RT-PCR corroborated all major findings from the
microarray analysis in two separate patient cohorts. Expression of
several inflammatory cytokine genes including interleukin 1ß,
interleukin 8, and tumor necrosis factor were highly increased in low
HDL-C subjects.
Conclusions- The activated proinflammatory state of monocytes and MDM
in low HDL-C subjects constitutes a novel parameter of risk associated
with HDL deficiency, related to altered expression of metallothionein
genes and the reciprocal regulation of PPAR and PPAR.
We demonstrate that cholesterol loaded monocyte-derived macrophages
from low HDL-C subjects exhibit a complex inflammatory gene response,
related to altered expression of PPAR, PPAR, and a cluster of
metallothionein genes. Our results suggest that a heightened
macrophage inflammatory response may contribute to the
pathophysiological consequences of HDL deficiency.
Andrew B. Chung, MD/PhD
It is the presence of visceral adipose tissue (VAT) that lowers our
HDL.
HDL deficiency is metabolic syndrome (MetS).
MarilynMann
wrote:
>
> "Unlike the 2PD-OMER Approach, weight loss diets can't be combined
>
> - Show quoted text -
Low HDL can also be due to hereditary factors.
Marilyn
Andrew B. Chung, MD/PhD
In industrialized countries, very rarely so that when it occurs, it
would not be called HDL deficiency but rather familial LCAT
deficiency.
May GOD bless you in HIS mighty way making you hungrier than ever.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://ABChung.LiveJournal.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
MarilynMann
> In industrialized countries, very rarely so that when it occurs, it
> would not be called HDL deficiency but rather familial LCAT
> deficiency.
>
I believe "low HDL" can mean different things in different contexts.
m not up on familial LCAT deficiency, but in the article I cited they
seem to be looking at a broader group of subjects:
Selection of Low HDL-C Subjects and Controls
Low HDL-C subjects were selected from consecutive referrals to the
Heart Institute Lipid Clinic based on the following criteria: White,
untreated values for HDL-C <5th%ile, TG <95th%ile (most <75th%ile),
LDL-C <75th%ile adjusted for age and sex. Exclusion criteria included
diabetes and clinical conditions or medications causative of low HDL.
Control subjects were healthy normolipemic volunteers of the same
ethnic background recruited from Ottawa region. The study was approved
by the University of Ottawa Heart Institute Human Research Ethics
Committee, and written informed consent was obtained from all
participants. Further details are provided in supplemental Table I and
supplemental methods.
Some of the low HDL-C subjects had an identified mutation and some
didn't.
Marilyn
Andrew B. Chung, MD/PhD
> Andrew, in the Holy Spirit, boldly wrote:
>
Because they have not explicitly written that they excluded folks with
metabolic syndrome (MetS), their low HDL-C subjects are, for all
intents and purposes, subjects with MetS, which is very common in
industrialized countries where overeating is rampant.
May GOD bless you in HIS mighty way making you hungrier than ever.
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://ABChung.LiveJournal.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets"
MarilynMann
> Because they have not explicitly written that they excluded folks with
> metabolic syndrome (MetS), their low HDL-C subjects are, for all
> intents and purposes, subjects with MetS, which is very common in
> industrialized countries where overeating is rampant.
>
I agree that they did not exclude people with metabolic syndrome,
although the BMI of the low HDL subjects did not differ significantly
from controls.
Marilyn
Andrew B. Chung, MD/PhD
> Andrew, in the Holy Spirit, boldly wrote:
>
> > metabolic syndrome (MetS), their low HDL-C subjects are, for all
> > intents and purposes, subjects with MetS, which is very common in
> > industrialized countries where overeating is rampant.
> >
>
> I agree that they did not exclude people with metabolic syndrome,
> although the BMI of the low HDL subjects did not differ significantly
> from controls.
There are plenty of "normal" BMI folks running around with MetS.
It is VAT and not BMI that causes MetS.
MarilynMann
> On Jun 15, 1:39 pm, "Andrew B. Chung, MD/PhD" >
>
> > Because they have not explicitly written that they excluded folks with
> > metabolic syndrome (MetS), their low HDL-C subjects are, for all
> > intents and purposes, subjects with MetS, which is very common in
> > industrialized countries where overeating is rampant.
>
>
HDL in persons with CAD has been found to differ from HDL in persons
without CAD:
Vaisar et al., Shotgun proteomics implicates protease inhibition and
complement activation in the antiinflammatory properties of HDL
J. Clin. Invest. 117:746-756 (2007).
HDL lowers the risk for atherosclerotic cardiovascular disease by
promoting cholesterol efflux from macrophage foam cells. However,
other antiatherosclerotic properties of HDL are poorly understood. To
test the hypothesis that the lipoprotein carries proteins that might
have novel cardioprotective activities, we used shotgun proteomics to
investigate the composition of HDL isolated from healthy subjects and
subjects with coronary artery disease (CAD). Unexpectedly, our
analytical strategy identified multiple complement-regulatory proteins
and a diverse array of distinct serpins with serine-type endopeptidase
inhibitor activity. Many acute-phase response proteins were also
detected, supporting the proposal that HDL is of central importance in
inflammation. Mass spectrometry and biochemical analyses demonstrated
that HDL3 from subjects with CAD was selectively enriched in apoE,
raising the possibility that HDL carries a unique cargo of proteins in
humans with clinically significant cardiovascular disease.
Collectively, our observations suggest that HDL plays previously
unsuspected roles in regulating the complement system and protecting
tissue from proteolysis and that the protein cargo of HDL contributes
to its antiinflammatory and antiatherogenic properties.
Marilyn
MarilynMann
wrote:
> MarilynMann wrote:
> > Andrew, in the Holy Spirit, boldly wrote:
>
> > > Because they have not explicitly written that they excluded folks with
> > > metabolic syndrome (MetS), their low HDL-C subjects are, for all
> > > intents and purposes, subjects with MetS, which is very common in
> > > industrialized countries where overeating is rampant.
>
> > I agree that they did not exclude people with metabolic syndrome,
> > although the BMI of the low HDL subjects did not differ significantly
> > from controls.
>
> There are plenty of "normal" BMI folks running around with MetS.
>
You are right that some of the low HDL folks may have had MetS, but
some of the controls may have had it as well. It is possible that
more of the former had MetS than of the latter, but we really do not
know that.
Marilyn
Andrew B. Chung, MD/PhD
> Andrew, in the Holy Spirit, boldly wrote:
> > MarilynMann wrote:
> > > Andrew, in the Holy Spirit, boldly wrote:
> >
> > > > Because they have not explicitly written that they excluded folks with
> > > > metabolic syndrome (MetS), their low HDL-C subjects are, for all
> > > > intents and purposes, subjects with MetS, which is very common in
> > > > industrialized countries where overeating is rampant.
> >
> > > I agree that they did not exclude people with metabolic syndrome,
> > > although the BMI of the low HDL subjects did not differ significantly
> > > from controls.
> >
> > There are plenty of "normal" BMI folks running around with MetS.
>
> You are right that some of the low HDL folks may have had MetS, but
> some of the controls may have had it as well.
It is likely that most if not all the low HDL folks have MetS.
> It is possible that
> more of the former had MetS than of the latter, but we really do not
> know that.
The higher levels of inflammatory cytokines in the former would inform
us that the low HDL have enough VAT to have MetS.
MarilynMann
> x-no-archive: yes
>
> MarilynMann wrote:
> > Low HDL can also be due to hereditary factors.
>
>
> Mine tendency was inherited, my formerly low HDL was due to low fat diet.
>
> Once I low carbed, it doubled to 68 and has stayed between 60-70 for
> almost a decade now, after a decade at 34.
>
> Susan
Sounds like you're doing well.
Marilyn
MarilynMann
> lab tested two weeks after switching from Ornish to low carb. My HDL
> had doubled, and my TGLs dropped from 259 to about 109, IIRC. My LDL
> dropped from about 200 to 132.
>
> My TGLs are currently 63, HDL 60, LDL 149.
>
> Susan
Interesting.
kevinbe...@yahoo.ca
wrote:
>
> "Unlike the 2PD-OMER Approach, weight loss diets can't be combined
> with well-balanced diets"http://HeartMDPhD.com/Love/TheTruth
Since you seem to believe in Jesus so much, in His name, why don't
you take a few minutes to translate your incomprehensible gobble-de-
gook
into something that non-medical people could actually understand? For
example, instead of the pretentious "Visceral Adipose Tissue", why
don't
you just simply say "belly fat"? People who hide behind big words are
generally
trying to mask either the unimportant ideas, or that they are trying
to lie to
your face.
Jesus spoke plainly; you speak like a pretentious blowhard. Which is
why
I tend to ignore most of your posts.
Andrew B. Chung, MD/PhD
> you take a few minutes to translate your incomprehensible gobble-de-
> gook
> into something that non-medical people could actually understand?
It would take several hours to translate the content in these
abstracts into something that non-medical people can unequivocably
understand.
> For example, instead of the pretentious "Visceral Adipose Tissue", why
> don't
> you just simply say "belly fat"?
Because it would not be accurate.
> People who hide behind big words are
> generally
> trying to mask either the unimportant ideas, or that they are trying
> to lie to
> your face.
VAT is not a big word and it does sound like FAT.
> Jesus spoke plainly; you speak like a pretentious blowhard.
Actually, I have not been speaking here.
> Which is why I tend to ignore most of your posts.
You have the free will that GOD has elected to generously give all
souls per HIS infinite and perfect free will.
The brethren of LORD Jesus Christ are neither perfect nor more
special...
... we are simply forgiven by GOD:
http://www.interviewwithgod.com/forgiven/
May you wisely choose to do be forgiven too by publicly declaring with
your mouth that "Jesus is LORD:"
http://HeartMDPhD.com/HolySpirit/TheWay
Prayerfully in Jesus' awesome love,
Andrew <><
--
Andrew B. Chung, MD/PhD
http://ABChung.LiveJournal.com
"Unlike the 2PD-OMER Approach, weight loss diets can't be combined
with well-balanced diets."
http://HeartMDPhD.com/Love/TheTruth
The Rev Dr Hugh Jarse NLAHN
wrote:
No, just typing, like a 12 year old kid who has been caught stealing
dad's beer from the fridge.