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OK, I'm still thinking ;-) but this is what I've figured out so far:

Males are VERY responsive to anti-androgen (& 5-alpha reductase inhibitor) therapies. While these treatments work, they may also reduce libidio to unsatisfactory levels and possibly inhibit muscle growth. Therefore, it appears that when dealing with males, from what studies I've read and the testimonies or anecdotal evidence on these boards, males do best when focusing on managing their sugar, lipid, and inflammatory product levels. Focusing on one or all three, may result in a reduction in testosterone, but more specifically WILL result in a reduction in inflammatory products.

Basically, what I see that's interesting about the DGAT is that it's controlled by Peroxisome Proliferator-Activated Receptors (PPAR). These receptors, along with Insulin-like Growth Factor-1 (IGF-1) are upregulated during the production of acne and these are responsible for a variety of functions including lipid metabolism. However, there are 3 forms, and these forms have very specific functions, aside from production of lipids. Yet, according to one study, done back in the 1998, each one of these forms has a role in the amount of lipids produced:

PPAR-beta/delta - 95%
PPARgamma - 66%
PPARalpha - 20%

PPARgamma + DHT = 70%
DHT = 25%
Control = 11%


So based on that it looks like you really want to get is the beta/delta (over DHT) as it's also implicated in athersclerosis, yet it's the least understood of them. However, another study in 2004 showed that upregulation of PPARgamma & PPARalpha could actually inhibit lipid production so this is one full text I need to grab a copy of:


Furthermore, in a 2003 study PPARs were also implicated in keritinocyte formation. Since it's not just about cell hyperproliferation but also hyperkeritinzation thats leads us to the theory of developing clogged pores in the formation of acne, it's interesting to note that again PPAR-alpha and PPAR-gamma are less involved than PPAR-beta/delta and this is much better explained by reading the following:

[quote]Br J Dermatol. 2003 Aug;149(2):229-36. Related Articles, Links

[b]Peroxisome proliferator-activated receptors in cutaneous biology.[/b]

Kuenzli S, Saurat JH.

Department of Dermatology, University Hospital, Geneva, Switzerland.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of target genes involved in many cellular functions including cell proliferation, differentiation and immune/inflammation response. The PPAR subfamily consists of three isotypes: PPAR alpha, PPAR beta/delta and PPAR gamma, which have all been identified in keratinocytes. PPAR beta/delta is the predominant subtype in human keratinocytes, whereas PPAR alpha and PPAR gamma are expressed at much lower levels and increase significantly upon keratinocyte differentiation. PPAR beta/delta is not linked to differentiation, but is significantly upregulated upon various conditions that result in keratinocyte proliferation, and during skin wound healing. In vitro and in vivo evidence suggests that PPARs appear to play an important role in skin barrier permeability, inhibiting epidermal cell growth, promoting epidermal terminal differentiation and regulating skin inflammatory response by diverse mechanisms. These proprieties are pointing in the direction of PPARs being key regulators of skin conditions characterized by hyperproliferation, inflammatory infiltrates and aberrant differentiation such as psoriasis, but may also have clinical implications in inflammatory skin disease (e.g. atopic dermatitis), proliferative skin disease, wound healing, acne and protease inhibitor associated lipodystrophia.

[url=][/url] [/quote]

After I found these, I found a few other articles and was wondering if Accutane played some role here as well since it does inhibit IGF-1. Granted, accutane also has the ability to increase insulin resistance and as such one can develop a hyperlipidic state while on it. Yet, despite that, I've found that there's a connection with the retinoic acid and retinoid X receptors and PPARs (they bind together) and since accutane (13-cis retinoic acid, isotretinion) & all trans retinoic acid (orally converted retinA) upregulates these receptors they may indeed be connected. In fact I found that ďAn activated PPAR must form a hetrodimer with the obligate cofactor retinoid X receptor (RXR) to interact with a peroxisome proliferator responsive element (PPRE) of a target gene and to regulate transcriptional expression.Ē Which seems to support the theory that these two must work together. If so that would explain why Iíve bumped into PPARalpha/RXR-alpha and PPAR-gamma/RXR-gamma complexesÖhmm. Thoughts?



Now, this article further defines the roles of PPARs:
[quote]PPAR alpha is a key regulator of fatty acid beta-oxidation, participates in development of inflammatory reaction and atherosclerosis formation. Main effects of fibrates are mediated through PPAR alpha activation. PPAR gamma plays important role in lipid metabolism, processes of cell differentiation and growth, participates in glucose utilization and mechanisms of insulin resistance.


It goes on to say again, they know that PPAR-beta/delta has a role but they don't specifically know what and further studies suggest that it increases athersclerosis, obesity and other aspects of metabolic syndrome. Whereas, PPAR-gamma inhibits these aspects of metabolic syndrome and as such PPAR-gamma agonists are being used to treat associated conditions.

Now, based on the above, this is what my theory is involving either agonists or co-activators for PPARs:

[B]PPAR-alpha[/B] agonists (20% lipid production) [U]slightly[/U] boost DGAT1 & inhibit DGAT2 (Diet, Fish Oil, Fibrates, Niacin, Sesamin, Green Tea, DHEA-S). While GPA / Ŗ-guanadinopropionic acid acts as a co-activator.

[B]PPAR-beta/delta[/B] agonists (95% lipid production) boost DGAT1 & inhibit DGAT2 - ???? (Saturated Fats, Trans Fats, Insulin Resistance, Androgens, Inflammatory Prostaglandins (PGE2))

[B]PPAR-gamma[/B] agonists (66% lipid production & inhibits cytokines) boost DGAT2 & inhibit DGAT1 - ???? (Diet, Insulin Sensitizers (Glitizones), Red Sage / Salvia Miltiorrhiza extract ?, Fenofibrate, Anti-inflammatory Prostaglandins (PGJ2, PGE1?) GPA is a co-activator .

These PPARs are still rather confusing. The studies mention only 3 forms yet some studies will specifically say that activation of PPAR-beta (leans on the negative), PPAR-delta (leans on the positive) or PPAR-beta/delta (leans on the negative) resulting in differing outcomes....sigh. Considering how complex this is, as there appears to be trade-offs for each PPAR, and since we know that PPAR gamma & alpha agonists suppress lipid production, we can find drugs or supplements that either work as PPAR-beta/delta antagonists or that work as PPAR alpha & gamma agonists.

So, when we think of PPAR-gamma agonists, what comes to mind? I suppose Phenogen may be one of these, but if concerned about weight loss, perhaps you may want to look into [B]Avandia[/B] instead. This was something that I took for a little over a year and if you are also concerned about weight loss/muscle gains while following an anti-inflammatory, anti-proliferative, & anti-androgenic type diet, this will probably put weight on ya ;-) Several other female & male (acne sufferers), including myself, have gained weight from taking this drug. In fact, I gained 5lbs for every 2mg of Avandia I was on....really quickly. Now some say it's water weight but other studies said that itís fat, but that it's distributed in more favorable areas (like my butt) =) In deed, considering that Iím underweight, I was saddened when I went off of the avandia as I almost immediately lost those 10lbs. Nonetheless, it's good to know that I don't "need" it, if I follow my diet properly, but this may be an option for some of you.

Thereís a few other supplements that Iím trying to catagorize, but Iím having trouble with. NAC is popular but it doesnít fall into any of the above categories. Iím tempted to think that B5 may be a co-activator on some level but Iím having trouble finding the supporting evidence for this as well. Since NAC & B5 are both used to produce Co-enzyme A, whenever I do a search I keep finding CoA products but it seems like they arenít in favor of inhibiting DGAT1. Clarifcations please Paracelsus?


P.S. What do you mean by "on" or "off" in terms of GPA?

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