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Science Forum Index » Life Extension Forum » Niacin, torcetrapib, HDL and mortality...
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| Thomas Carter... |
 Posted: Sat Jun 07, 2008 7:09 pm |
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Guest
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Hi,
Exercise, statin drugs, alcohol, krill oil, and a few
other interventions may cause a small increase in HDL-C, the “good”
cholesterol, but only niacin and torcetrapib have been convincingly
proven to raise it substantially. Long term use of niacin has reduced
cardiovascular, and total mortality in randomized trials, and is
prescribed by doctors when indicated. Torcetrapib caused a 60%
increase of mortality in a large phase III trial which was stopped
early in Feb. ’08.
CETP is the plasma enzyme that transfers cholesterol from
HDL to LDL. Since “good” cholesterol is defined as that which is found
on the HDL molecule, anything that interferes with this process will
raise “good” cholesterol and lower “bad” cholesterol, which is defined
as that which is found on LDL. And just as certainly it will interfere
with the function of HDL. Since torcetrapib works by inhibiting CETP
it predictably caused the excess mortality mentioned and was dropped
by Pfizer. Low CETP activity due to genetic mutations had been
associated with longevity as well as increased heart attacks, so
Pfizer may have been justified to launch this risky trial.
ATP synthase, also known as complex five of the
mitochondrial electron transfer chain has a component called the beta
chain that when sent to the plama membrane of liver cells, captures
HDL importing it for catabolism. Niacin inhibits this pathway by an
unknown mechanism. Thus niacin increases “good” cholesterol by keeping
more HDL molecules in the plasma where they function, while
torcetrapid increases “good” cholesterol by overloading the HDL
molecules so they can’t function as well. This time theoretical
considerations have been born out by observation.
Niacin doesn’t reduce expression of ATP synthase beta
chain, it simply reduces the amount sent to the plasma membrane. This
fact may enhance ATP synthase activity, increasing mitochondrial
function and reducing free radical production. Niacin related
molecules appear to do just this and one, niacinamide is also
increased by niacin supplementation. PMID: 17878764 and PMID:
17691278 The second abstract mentions an increase in the state 3/
state 4 ratio. For those who don’t remember the lively discussion we
had years ago on mitochondrial function state 3 is the clean, ATP
producing state, while four produces more free radicals.
Thomas
1: Curr Opin Cardiol. 2008 Jul;23(4):393-8.Related Articles, Links
Nicotinic acid: recent developments.
Kamanna VS, Vo A, Kashyap ML.
Atherosclerosis Research Center, Department of Veterans Affairs
Healthcare System, Long Beach, California, USA.
PURPOSE OF REVIEW: To review the recent progress in
niacin research that is made in two major areas: new preparations to
decrease flushing and niacin's mechanism of action. RECENT FINDINGS:
Flushing, an adverse effect of niacin, results from GPR109A-mediated
production of prostaglandin D2 and E2 in Langerhans' cells which act
on DP1 and EP2/4 receptors in dermal capillaries causing their
vasodilatation. DP1 receptor antagonist (laropiprant) attenuates the
niacin flush in animals and humans. A reformulated preparation of
extended-release niacin lowers flushing compared with the extended-
release niacin (Niaspan, Abbott Laboratories, Chicago, Illinois, USA).
Aspirin pretreatment attenuates flushing from Niaspan.Recent data on
niacin's mechanism of action indicate that it directly inhibits
hepatic diacylglycerolacyl transferase 2 resulting in an inhibition of
triglyceride synthesis and decreased apolipoprotein B-containing
lipoproteins; niacin, by inhibiting the surface expression of hepatic
ATP synthase beta chain, decreases the hepatic holoparticle high-
density lipoprotein catabolism and raises high-density lipoprotein
levels; and niacin increases redox potential in arterial endothelial
cells resulting in the inhibition of redox-sensitive genes. SUMMARY:
Recent developments suggest that the niacin receptor GPR109A is
involved in flushing, but it does not explain multiple actions of
niacin. Actions of niacin on diacylglycerolacyl transferase 2, ATP
synthase beta chain, and redox state may explain the multiple actions
of niacin. PMID: 18520725
2: J Lipid Res. 2008 Jun;49(6):1195-201. Epub 2008 Mar 3.Related
Articles, Links
Niacin inhibits surface expression of ATP synthase {beta} chain in
HepG2 cells: implications for raising HDL.
Zhang LH, Kamanna VS, Zhang MC, Kashyap ML.
Atherosclerosis Research Center, Veterans Administration Healthcare
System, Long Beach, CA; and Department of Medicine, University of
California, Irvine, CA.
Niacin is an effective agent for raising HDL, but
its cellular target sites are largely unknown. We examined effects of
niacin on the surface expression of ATP synthase beta chain, a newly
described HDL/apolipoprotein A-I (apoA-I) receptor for HDL
endocytosis, in HepG2 cells. A significant amount of immunodetectable
beta chain was observed on the surface of HepG2 cells, which was
competitively displaced by apoA-I. Niacin treatment reduced the
surface expression of beta chain in HepG2 cells by approximately 27%,
and decreased (125)I-labeled HDL uptake up to approximately 35%.
However, nicotinamide, a niacin metabolite that does not have clinical
lipid effects, exhibited weaker inhibition on the beta chain cell
surface expression, and failed to show inhibitory action on (125)I-
labeled HDL uptake. Furthermore, anti-beta chain antibody
significantly reduced (125)I-labeled HDL uptake and abolished the
inhibitory effect of niacin. Niacin did not change beta chain mRNA
expression. These data suggest that niacin inhibits cell surface
expression of the ATP synthase beta chain, leading to reduced hepatic
removal of HDL protein, thus implicating a potential cellular target
for niacin action to raise HDL.
PMID: 18316796 |
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