Exercise in a Pill
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I would like to say that I did NOT read the other post before posting and my comment was totally serious. I was NOT trolling or trying to start anything by any means!
Don'twannagetfuckingbanned/10
some info but the best is to try it yourself
Discussion
During the past decade the role of the orphan nuclear receptors PPAR***945; and PPAR***947; in the regulation of lipid metabolism has been clearly established through their association with the fibrate and glitazone drugs, respectively (1). There have been several tantalizing clues that PPAR***948; also may modulate aspects of lipid homeostasis: PPAR***948; binds to many of the same fatty acids as the other subtypes (2), signifying that it also may be a dietary lipid sensor; L-165041, a weak nonselective PPAR***948; agonist (1), raised total cholesterol levels in db/db mice (37); and PPAR***948; null mice displayed a reduction in the size of adipose tissue depots (38), although no lipid phenotype was reported. However, in the absence of potent and selective ligands, the physiological role of PPAR***948; has remained an enigma. In this report, we have described a truly selective PPAR***948; agonist, GW501516. Using GW510516 as a chemical tool, we have provided evidence that PPAR***948; increases cholesterol efflux from cells, in part, through an increase in the expression of the ABCA1 reverse cholesterol transporter. These data suggest that PPAR***948; is an important regulator of cholesterol metabolism with unique pharmacology that distinguishes it from the other PPAR subtypes.
There are significant differences in the regulation of lipid metabolism in rodents compared with humans (39). This is highlighted by the fact that there is no single rodent model of dyslipidemia in which both PPAR***945; and PPAR***947; agonists are active (40). We chose to study the pharmacology of a PPAR***948; ligand in obese rhesus monkeys where the lipid profile more closely matches that seen in humans (19). In these primates, GW501516 has beneficial effects on multiple cardiovascular risk factors, including lipoprotein size and composition, resulting in a potentially less atherogenic lipid profile (6). These changes, which include a marked increase in HDLc, are consistent with an increased flux of cholesterol from peripheral tissues to nascent HDL particles. Patients with Tangier disease and familial hypoalphalipoproteinia have low circulating levels of HDLc and high triglycerides due to mutations in the ABCA1 gene (11). Fibroblasts from these patients show a reduced capacity for cholesterol efflux, which correlates with the decrease in HDLc and an increased risk of cardiovascular disease (15). Because, GW501516 increases ABCA1 expression, promotes cholesterol efflux from peripheral cell types, and raises HDLc in primates, it appears that activation of PPAR***948; provides a novel mechanism for promoting reverse cholesterol transport (9). Additional studies will be required, however, to determine the global effect of GW501516 on cholesterol flux from peripheral tissues to the liver.
Fibrates are a class of drugs that have been used for decades for their beneficial effects on serum lipids. Although fibrates are predominantly triglyceride-lowering drugs that only modestly raise HDLc (19, 36), clinical trials have shown that they lower the incidence of atherosclerosis and coronary artery disease in patients with normal levels of LDLc (36, 41). Most fibrate drugs are only weakly active on human PPAR***945; and show low selectivity over human PPAR***948; and PPAR***947; (1). It was recently reported that the experimental fibrate drug Wy14,643 induces ABCA1 expression and cholesterol efflux from macrophages (42). However, at the concentrations used in the study (50 ***956;M), Wy14,643 has significant PPAR***948; activity [EC50 = 35 ***956;M for human PPAR***948; (1)]. Using compounds that are selective for each of the three PPAR subtypes, we have now shown that their relative ability to induce ABCA1 expression is PPAR***948; > PPAR***947; > PPAR***945;. These data argue that the reported effects (42) of high doses of fibrates on cholesterol efflux are mediated primarily through PPAR***948;. Glitazone PPAR***947; agonists also were reported to increase ABCA1 expression through the induction of LXR***945; expression (42, 43). Interestingly, we observed no consistent increase in LXR***945; expression with GW501516 (Table 1) suggesting that alternate mechanisms may contribute to the regulation of ABCA1 expression by PPAR***948; agonists.
The therapeutic effects of fibrates are due, in part, to their effects on hepatic gene expression mediated by PPAR***945; (36). In particular, decreases in the expression of apoCIII have been associated with the triglyceride-lowering activity of PPAR***945; agonists (44–46). We were surprised to find that GW501516 raised serum apoCIII levels in the obese rhesus monkeys. Although both PPAR***945; and PPAR***948; agonists lower triglycerides in primates, GW501516 has a greater effect on HDLc compared to a fibrate. It is possible that the observed increase in apoCIII after activation of PPAR***948; is due to an increase in the number of these apos associated with the HDL particles. In addition, GW501516 does not affect apoA1 or apoCIII mRNA levels in human hepatocytes (data not shown), providing further evidence that changes in hepatic gene expression are unlikely to explain the changes in serum HDLc or triglycerides.
Hyperinsulinemia and the lipid triad of low HDLc, small LDL particles, and elevated serum triglycerides are characteristics of dyslipidemia associated with the metabolic syndrome X (6, 7). Individuals with this atherogenic lipoprotein phenotype have a higher incidence of premature coronary artery disease (6). Our results demonstrate that PPAR***948; agonists are likely to have beneficial effects on the lipid triad and the atherogenic particle composition through a mechanism that increases cholesterol flux from peripheral tissues. These activities, combined with the benefit of lowering serum insulin levels, suggest that PPAR***948; agonists may be powerful drugs for decreasing the incidence of cardiovascular disease associated with the metabolic syndrome X.
Previous SectionNext Section
Acknowledgments
We thank Lisa Leesnitzer for PPAR***948; binding data, Jon Collins for unpublished data on GW3965, Peter Brown for unpublished data on GW7647, Annette Graham (Royal Free Hospital, London) for assistance in developing the cholesterol efflux assay, Theresa Alexander, Michelle Izuka, Wallace Evans, and Karen Brocklehurst for assistance with the primate study, and Jane Binz for analysis of clinical chemistries. We also thank Henry Ginsberg (Columbia University), David Hassall, and Jeff Cobb for comments on the manuscript.
Previous SectionNext Section
Footnotes
*
***8629;¶ To whom reprint requests should be addressed at: GlaxoSmithKline, Five Moore Drive, NTH-M1421, Research Triangle Park, NC 27709-3398. E-mail: tmw20653@gsk.com.
*
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations
PPAR,
peroxisome proliferator-activated receptor;
RXR,
9-cis-retinoic acid receptor;
HDL,
high density lipoprotein;
HDLc,
HDL cholesterol;
ABC,
ATP binding cassette;
LDL,
low density lipoprotein;
VLDL,
very low density lipoprotein;
apo,
apolipoprotein;
LXR,
liver X receptor
* Received January 12, 2001.
* Copyright © 2001, The National Academy of Sciences
Previous Section
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Discussion
During the past decade the role of the orphan nuclear receptors PPAR***945; and PPAR***947; in the regulation of lipid metabolism has been clearly established through their association with the fibrate and glitazone drugs, respectively (1). There have been several tantalizing clues that PPAR***948; also may modulate aspects of lipid homeostasis: PPAR***948; binds to many of the same fatty acids as the other subtypes (2), signifying that it also may be a dietary lipid sensor; L-165041, a weak nonselective PPAR***948; agonist (1), raised total cholesterol levels in db/db mice (37); and PPAR***948; null mice displayed a reduction in the size of adipose tissue depots (38), although no lipid phenotype was reported. However, in the absence of potent and selective ligands, the physiological role of PPAR***948; has remained an enigma. In this report, we have described a truly selective PPAR***948; agonist, GW501516. Using GW510516 as a chemical tool, we have provided evidence that PPAR***948; increases cholesterol efflux from cells, in part, through an increase in the expression of the ABCA1 reverse cholesterol transporter. These data suggest that PPAR***948; is an important regulator of cholesterol metabolism with unique pharmacology that distinguishes it from the other PPAR subtypes.
There are significant differences in the regulation of lipid metabolism in rodents compared with humans (39). This is highlighted by the fact that there is no single rodent model of dyslipidemia in which both PPAR***945; and PPAR***947; agonists are active (40). We chose to study the pharmacology of a PPAR***948; ligand in obese rhesus monkeys where the lipid profile more closely matches that seen in humans (19). In these primates, GW501516 has beneficial effects on multiple cardiovascular risk factors, including lipoprotein size and composition, resulting in a potentially less atherogenic lipid profile (6). These changes, which include a marked increase in HDLc, are consistent with an increased flux of cholesterol from peripheral tissues to nascent HDL particles. Patients with Tangier disease and familial hypoalphalipoproteinia have low circulating levels of HDLc and high triglycerides due to mutations in the ABCA1 gene (11). Fibroblasts from these patients show a reduced capacity for cholesterol efflux, which correlates with the decrease in HDLc and an increased risk of cardiovascular disease (15). Because, GW501516 increases ABCA1 expression, promotes cholesterol efflux from peripheral cell types, and raises HDLc in primates, it appears that activation of PPAR***948; provides a novel mechanism for promoting reverse cholesterol transport (9). Additional studies will be required, however, to determine the global effect of GW501516 on cholesterol flux from peripheral tissues to the liver.
Fibrates are a class of drugs that have been used for decades for their beneficial effects on serum lipids. Although fibrates are predominantly triglyceride-lowering drugs that only modestly raise HDLc (19, 36), clinical trials have shown that they lower the incidence of atherosclerosis and coronary artery disease in patients with normal levels of LDLc (36, 41). Most fibrate drugs are only weakly active on human PPAR***945; and show low selectivity over human PPAR***948; and PPAR***947; (1). It was recently reported that the experimental fibrate drug Wy14,643 induces ABCA1 expression and cholesterol efflux from macrophages (42). However, at the concentrations used in the study (50 ***956;M), Wy14,643 has significant PPAR***948; activity [EC50 = 35 ***956;M for human PPAR***948; (1)]. Using compounds that are selective for each of the three PPAR subtypes, we have now shown that their relative ability to induce ABCA1 expression is PPAR***948; > PPAR***947; > PPAR***945;. These data argue that the reported effects (42) of high doses of fibrates on cholesterol efflux are mediated primarily through PPAR***948;. Glitazone PPAR***947; agonists also were reported to increase ABCA1 expression through the induction of LXR***945; expression (42, 43). Interestingly, we observed no consistent increase in LXR***945; expression with GW501516 (Table 1) suggesting that alternate mechanisms may contribute to the regulation of ABCA1 expression by PPAR***948; agonists.
The therapeutic effects of fibrates are due, in part, to their effects on hepatic gene expression mediated by PPAR***945; (36). In particular, decreases in the expression of apoCIII have been associated with the triglyceride-lowering activity of PPAR***945; agonists (44–46). We were surprised to find that GW501516 raised serum apoCIII levels in the obese rhesus monkeys. Although both PPAR***945; and PPAR***948; agonists lower triglycerides in primates, GW501516 has a greater effect on HDLc compared to a fibrate. It is possible that the observed increase in apoCIII after activation of PPAR***948; is due to an increase in the number of these apos associated with the HDL particles. In addition, GW501516 does not affect apoA1 or apoCIII mRNA levels in human hepatocytes (data not shown), providing further evidence that changes in hepatic gene expression are unlikely to explain the changes in serum HDLc or triglycerides.
Hyperinsulinemia and the lipid triad of low HDLc, small LDL particles, and elevated serum triglycerides are characteristics of dyslipidemia associated with the metabolic syndrome X (6, 7). Individuals with this atherogenic lipoprotein phenotype have a higher incidence of premature coronary artery disease (6). Our results demonstrate that PPAR***948; agonists are likely to have beneficial effects on the lipid triad and the atherogenic particle composition through a mechanism that increases cholesterol flux from peripheral tissues. These activities, combined with the benefit of lowering serum insulin levels, suggest that PPAR***948; agonists may be powerful drugs for decreasing the incidence of cardiovascular disease associated with the metabolic syndrome X.
Previous SectionNext Section
Acknowledgments
We thank Lisa Leesnitzer for PPAR***948; binding data, Jon Collins for unpublished data on GW3965, Peter Brown for unpublished data on GW7647, Annette Graham (Royal Free Hospital, London) for assistance in developing the cholesterol efflux assay, Theresa Alexander, Michelle Izuka, Wallace Evans, and Karen Brocklehurst for assistance with the primate study, and Jane Binz for analysis of clinical chemistries. We also thank Henry Ginsberg (Columbia University), David Hassall, and Jeff Cobb for comments on the manuscript.
Previous SectionNext Section
Footnotes
*
***8629;¶ To whom reprint requests should be addressed at: GlaxoSmithKline, Five Moore Drive, NTH-M1421, Research Triangle Park, NC 27709-3398. E-mail: tmw20653@gsk.com.
*
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations
PPAR,
peroxisome proliferator-activated receptor;
RXR,
9-cis-retinoic acid receptor;
HDL,
high density lipoprotein;
HDLc,
HDL cholesterol;
ABC,
ATP binding cassette;
LDL,
low density lipoprotein;
VLDL,
very low density lipoprotein;
apo,
apolipoprotein;
LXR,
liver X receptor
* Received January 12, 2001.
* Copyright © 2001, The National Academy of Sciences
Previous Section
References
1. ***8629;
1. Willson T M,
2. Brown P J,
3. Sternbach D D,
4. Henke B R
(2000) J Med Chem 43:527–550, pmid:10691680.
CrossRefMedlineWeb of Science
2. ***8629;
1. Xu H E,
2. Lambert M H,
3. Montana V G,
4. Parks D J,
5. Blanchard S G,
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8. Lehmann J M,
9. Wisely G B,
10. Willson T M,
11. et al.
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CrossRefMedlineWeb of Science
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2. Evans R M
(1995) Cell 83:841–850, pmid:8521508.
CrossRefMedlineWeb of Science
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2. Foufelle F,
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4. Dauca M,
5. Wahli W
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Abstract
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2. Kennedy E,
3. Barrier P,
4. Ernst N D,
5. Grundy S M,
6. Leveille G A,
7. Van Horne L,
8. Williams C L,
9. Booth S L
(1998) Nutr Rev 56:S3–S28, pmid:9624878.
MedlineWeb of Science
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(2000) J Clin Invest 106:453–458, pmid:10953019.
MedlineWeb of Science
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(2000) Curr Opin Lipidol 11:597–602, pmid:11086332.
CrossRefMedlineWeb of Science
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Cobra Strike
New member
Cosagwhateveryourgayassnameis....you are posting worthless bullshit. If you were told to stay away then why are you here? You obviously didn't listen to whoever told you that so why would you listen here?
You know what....just shut up and put up then ya big bad ass killer....take the shit and whenever its gone and nothing happened to your skinny ass then go look in the mirror and realize how fuk'n stupid you really are
DPR....if you want to ban me for this post then whatever but if you read from the beginning this guy wants nothing but to fight on this thread and I'm not gonna sit here and let his dumb ass talk shit and get away with it.
You know what....just shut up and put up then ya big bad ass killer....take the shit and whenever its gone and nothing happened to your skinny ass then go look in the mirror and realize how fuk'n stupid you really are
DPR....if you want to ban me for this post then whatever but if you read from the beginning this guy wants nothing but to fight on this thread and I'm not gonna sit here and let his dumb ass talk shit and get away with it.
Cobra Strike
New member
Actually....IMO this asshole should get banned...this site doesn't need arogant pricks that can't contribute in any way, shape, or form but to disrespect the respected members...but I'm not a mod...just my 02
balboa270
Amateur Bodybuilder
From Master yoda ***8220;Size matters not, ... Look at me. Judge me by size, do you?***8221; ***8220;Ready are you? What know you of ready? For eight hundred years have I trained Jedi. My own counsel will I keep on who is to be trained. A Jedi must have the deepest commitment, the most serious mind. This one a long time have I watched. All his life has he looked away... to the future, to the horizon. Never his mind on where he was. Hmm? What he was doing. Hmph. Adventure. Heh. Excitement. Heh. A Jedi craves not these things. You are reckless.***8221; Sorry Cobra and cosodrdagalupus figured I'd break the ice
balboa270
Amateur Bodybuilder
Fuck not you again the 170 lb. keyboard warrior I told you I promise to make my sister quit picking on ya get over it
Gw1516
I have some clientele on this product there has been amazing results
Client 1 , is 61years of age, and has been on it for 5 days , within the first hour he had noticed his energy around the garden was great, and when he came yo work he could walk all flights of stairs @56 m high to the top and down like a young fit man..
weight loss to date let's call it 1 week 3kg
client 2, this is 36,6"3 and 125kg. could hardly wake on time for work and didn't really do much when he got there.. but no bs , energy through the roof and is working at my pace all day .
ps. no one has changed diet or drinking habits
Both man are taking 1 full dropper 1ml after breakfast. and also had noticeable wrinkle thinning around the eyes.
I am running Hexelerin much the same as GHRP6 but stronger , with 1ml of liquid Ostarine under my tong before bed , and am getting great gains and healing properties from it
I have some clientele on this product there has been amazing results
Client 1 , is 61years of age, and has been on it for 5 days , within the first hour he had noticed his energy around the garden was great, and when he came yo work he could walk all flights of stairs @56 m high to the top and down like a young fit man..
weight loss to date let's call it 1 week 3kg
client 2, this is 36,6"3 and 125kg. could hardly wake on time for work and didn't really do much when he got there.. but no bs , energy through the roof and is working at my pace all day .
ps. no one has changed diet or drinking habits
Both man are taking 1 full dropper 1ml after breakfast. and also had noticeable wrinkle thinning around the eyes.
I am running Hexelerin much the same as GHRP6 but stronger , with 1ml of liquid Ostarine under my tong before bed , and am getting great gains and healing properties from it
mecprolabs
New member
This is an excerpt from a recent article on GW501516:
A phase IV clinical study was completed in Australia in 2008. It assessed the application of GW5015156 in the treatment of high blood cholesterol in insulin resistance and obesity.
No adverse events were reported by the authors for the phase IV trials. The authors also cited two earlier clinical studies that showed no significant adverse effect of the drug, including liver or muscle responses in participants treated with GW501516.
A phase IV clinical study was completed in Australia in 2008. It assessed the application of GW5015156 in the treatment of high blood cholesterol in insulin resistance and obesity.
No adverse events were reported by the authors for the phase IV trials. The authors also cited two earlier clinical studies that showed no significant adverse effect of the drug, including liver or muscle responses in participants treated with GW501516.
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