PPAR Agonists for Life Extension?? WAS Re: Another Negative Antioxidant Life Span Study in Rodents
Michael
"Steve Harris" <sbha...@ix.RETICULATEDOBJECTcom.com> wrote in message news:<a72ui4$f1k$1...@nntp9.atl.mindspring.net>...
> "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message
> news:%m2l8.3636$Zr3.1...@news1.news.adelphia.net...
>
> > Have you seen the following? Unlike the PPAR gamma agonist rosiglitazone,
> > which, if I recall correctly has little or no effect on HDLc, this stuff
> > boosted HDLc by 80%.
Indeed, it's very much a key PROBLEM with the PPAR-g agonists that,
while increasing insulin sensitivity (largely in the adipose cells,
leading to weight gain of the bad kind), they also bugger up one's
lipid profile.
> >
> > Proc Natl Acad Sci U S A 2001 Apr 24;98(9):5306-11
> > A selective peroxisome proliferator-activated receptor delta agonist
> > promotes reverse cholesterol transport.
The very mild parallels between the results of this study and the
effects of CR have been absurdly (I dare say shamefully) overhyped as
representing a CR mimetic:
http://www.medserv.dk/print.php?sid=1222
>
>
> Interesting! We need something better than niacin. Hopefully this will
> lead to a new class of drug treatment.
Unfortunately, even as it increases HDL & reverse cholesterol
transport, PPAR-d appears to cause macrophages to suck up cholesterol
via the scavenger receptors, which wold be expected to be nastily
atherogenic:
J Biol Chem 2001 Nov 23;276(47):44258-65
The peroxisome proliferator-activated receptor delta promotes lipid
accumulation
in human macrophages.
Vosper H, Patel L, Graham TL, Khoudoli GA, Hill A, Macphee CH, Pinto
I, Smith
SA, Suckling KE, Wolf CR, Palmer CN.
... Drugs that activate PPARalpha [like fibrates] are effective in
lowering plasma levels of lipids and have been used in the management
of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and
are used in the management of type 2 diabetes. ...
In this report we demonstrate that ... a highly selective agonist of
PPARdelta (compound F) promotes lipid accumulation in primary human
macrophages and in macrophages derived from the human monocytic cell
line, THP-1.
Compound F increases the expression of genes involved in lipid uptake
and storage such as the class A and B scavenger receptors (SRA, CD36
[whose physiological target is modified LDL -MR]) and adipophilin.
PPARdelta activation also REPRESSES key genes involved in lipid
metabolism and efflux, i.e. cholesterol 27-hydroxylase and
apolipoprotein E.
We have generated THP-1 sublines that overexpress PPARdelta and have
confirmed that PPARdelta is a powerful promoter of macrophage lipid
accumulation.
These data suggest that PPARdelta may play a role in the pathology of
diseases associated with lipid-filled macrophages, such as
atherosclerosis, arthritis, and
neurodegeneration.
PMID: 11557774
-Michael
--
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