Jump to content
Acne.org
Search In
Find results that contain...
Find results in...
LabGirl81

Linoleic Acid Deravitives in the Epidermis

Okay I have nothing of any interest to post presently about this topic that I haven't already mentioned, but I'm going to a NYSCC (New York Society of Cosmetic Chemists) meeting on March 1st and this is the topic of the meeting: Linoleic Acid Deravitives in the Epidermis ...a topic that has come up in this board recently...the description of the seminar mentions ceramides and other lipids that contain linoleic acid and talks about how linoleic acid influences the water barrier function of the skin.....

The speaker is Dr. Phillip W. Wertz from the Dows Institute at the University of Iowa....he specializes in lipids and barrier function of skin and oral mucosa....

If I learn anything interesting or pertaining to acne I'll post it....I'll be able to ask questions at the meeting and should be able to ask what he thinks about the deficiency of linoleic acid and resulting impaired water barrier function seen in acneic skin.......

They usually have a cocktail hour at these meetings....so I'll try not to drink too much this time.... :angel:

Share this post


Link to post
Share on other sites

Okay so I went to this seminar last night......It was pretty interesting, because Dr. Wertz has done a ton of research about the physiology of the epidermis, specifically the lipids that make up the barrier function of the statum corneum. He talked about how the lipids in out diet influence the lipids found in the stratum corneum and how dietary deficencey usually accoutns for most of the deficencey of linoleic acid in the epidermis, and what linoleic acid's role is in the barrier function of epidermis....

I pretty much already knew most of the material he presented, but some of his more recent research has to do with the exact structure of the ceramides and how they're arranged into multiple intercellular lamellae that provide an efficient water barrier due to the crystalline array of the straight and predominantly saturated lipid chains on the acylceramides and acylglucosylceramides. Linoleic acid is important because it is esterfied at the w-hydroxy position on the acylcaramide. This is not only important to the formation of the crystalline array of lipid chains, but also to proper keratinization and the subsequent desquamation of keratinocytes as they proliferate to become coreocytes (keratinized calls of the stratum corneum). His researche actually goes way into this topic and I don't feel like typing much more so I'll post links to some of his studies.....

Essential fatty acids and acne

Skin lipids: an update

Dilutional effect of increased sebaceous gland activity on the proportion of linoleic acid in sebaceous wax esters and in epidermal acylceramides

Fatty acids of acylceramides from comedones and from the skin surface of acne patients and control subjects.

I did get a chance to talk to him and ask him what he thought about the localized deficiency of linoleic acid in the epidermis of acne patients and exactly what it had to do with the process of comedo formation. He suggested that it is actually caused by the fatty acids from the sebaceous lipids. When fatty acids derived from sebum become incorporated into comedonal acylceramides, they displace linoleate. That this process even affects the acylceramides of surface epidermis, more so in acne patients than in normal subjects (this is even seen in areas of the skin that don't have a high concentration of sebaceous glands, like the epidermal lipids from the legs)...

He asked if I had a PhD....I told him no, but I'm completley facinated by this topic...

He offered me a position to do a paid fellowship.....

Share this post


Link to post
Share on other sites

Great info, thanks LabGirl. And congrats on the fellowship offer, do you think you'll take it?

I have a few ?s I hope you can help with.

Where and how is linoleate produced from linoleic acid?

Why does a lack of linoleate induce hyperkeratosis in the cells of the follicular epithelium? Does linoleate have an inhibitory effect on keratin production by these cells and how does the signaling occur? Or do the chemicals that take the place of the decreased linoleate have a pro-keratinization affect?

What role do microbial (mainly P. acnes) lipases play in all this?

I often read that P. acnes lipases break down triglycerides in sebum into free fatty acids, which then irritate the cells of the follicular wall. But what exactly does irritation mean and why do the free fatty acids cause the irritation? Also, how exactly do the free fatty acids interact with the follicular wall cells?

Thanks, any insight will be hellpful...

Share this post


Link to post
Share on other sites

This is indeed great info, finding stuff like this on the net is difficult to say the least and i wholly believe this area of knowledge is the key to understanding and curing acne

I have a few questions of my own for anyone interested.

If the localised deficiency of linoleic acid is caused by over-production of sebum as apposed to some form of malfunction then is it not possible to just compensate by consuming higher levels of linoleic acid or the required precursors?

Also no-one responded to my last post :boohoo: so can anyone give me a reason why oral or topical conjugulated linoleic acid in a FFA form wouldn’t help to achieve this compensatation?

Is CLA too different to linolate / linoleic acid?

Share this post


Link to post
Share on other sites

Great info, thanks LabGirl. And congrats on the fellowship offer, do you think you'll take it?

Not too sure. I have to apply to the graduate program, which requires me to take the GRE for Biochemistry, Cell and Molecular Biology ( subjects I don't know much about). I have to see if I can get away with a Chemisrty GRE, since that was my field of study. I only took a general GRE for graduate school. So which ever way it works out, I'll have some studying to do....Plus I'm a Jersey girl, so Iowa would be like a totally different world to me. My family and boyfriend are here in Jersey....

But how often does an opportunity like that come along? It's the exact topic that I wan to research... I'm really torn right now....We do have some great schools in the area that I live in...Princeton, Columbia, ect....so maybe there's someting closer to home.........

I have a few ?s I hope you can help with.

Where and how is linoleate produced from linoleic acid?

The terms linoleate and linoleic acid are often used interchangably. Linoleic acid is a fatty acid (a carboxylic acid with a long hydrophobic tail). The suffix -ate on the end of a carboxylic acid refers to a carboxylic acid that has has lost a hydogen ion, leaving behind a negative charge on the oxygen. (think acetic acid and sodium acetate) Usually this negative oxygen is easily combines with a positively charged metal ion or in the case it can combine with alcohol molecules to make esters.....like the combination between potassium and linoleic acid forms potassuim linoleate (a soap), or the comination between retinol (an alcohol) and linoleic acid forms retinyl linoleate. The suffix -ate on refers to an ester with an an alcohol or a metal salt of a carboxylic acid......Ahh O-chem....I miss that stuff.......

Why does a lack of linoleate induce hyperkeratosis in the cells of the follicular epithelium? Does linoleate have an inhibitory effect on keratin production by these cells and how does the signaling occur? Or do the chemicals that take the place of the decreased linoleate have a pro-keratinization affect?

I figured you'd had to make me think at some point (If you don't already know...I'm a blonde). My understanding is that if linoleic acid is deficent in the epidermis and other n,6-9 fatty acids are more prevalent (like oleic acid) than they can substitute for linoleate the w-hydroxyl postion on the epidermal ceramides.

The linoleic acid is very important to the structure of the intercellular lamaller lipid structure that makes up the skin's barrier function, but it also has some chemical importance. It is the only n,6-9 fatty acid that is has the stereochemical configuration undergo hydroxylation by a very specific lipoxygenase to monohydroxyoctadecadienoic acid and trihydroxyoctadecenoic acid which coincides with the production of peroxides that activate enzymes that mediate the corification process. I'm seeing a possibility for a feedback mechanism here (need to look into it more). It is seen that when other unsaturated fatty acids like oleic acid or palmitoleic acid are applied topically to mouse skin induced an abnormal calcium distribution in the epidermis. Which suggests that unsaturated fatty acids in sebum alter the calcium dynamics in epidermal keratinocytes and can induce abnormal follicular keratinization. I think you were the one who posted that study. My reasoning for this is that the epidermal ceramides actually demonstrate an uptake of these fatty acids and they become esterfied to the w-hydroxyl postion on the acylceramides and acylglucosylceramides.

Acne is usually always associated with an increase in sebum production. According to Wertz and his colleuges:

The sebaceous glands secrete continuously, producing sebum that consists predominantly of triglycerides, wax esters, and squalene. High rates of sebum production per sebocyte result in low levels of linoleate in the sebaceous esters, subjecting the follicular epithelium to essential fatty acid deficiency and the characteristic hyperkeratosis that results in comedo formation.

In some later research they determined that that fatty acids derived from sebum become incorporated into comedonal acylceramides, displacing linoleate. This is most likely why acne parients also seem to almost always have a certain degree of impairment in their epidermal water barrier function...Sebum actually damages our epidermal barrier function!!!!

What role do microbial (mainly P. acnes) lipases play in all this?

I often read that P. acnes lipases break down triglycerides in sebum into free fatty acids, which then irritate the cells of the follicular wall. But what exactly does irritation mean and why do the free fatty acids cause the irritation? Also, how exactly do the free fatty acids interact with the follicular wall cells?

The lipases of p. acnes breakdown the triglycerides and wax esters in sebum into free fatty acids. If there is a defiency in linoleic acid (linoleate) in the sebacous lipids than the ceramides in in the intracellular space between the epidermal cells that line the follicular epithelium will esterify other more prevalent fatty acids like oleic acid at the w-hydroxyl postion on the ceramides (the same that appear on the surface of the skin also line the follicular walls). Since this deficency in linoleate causes a disruption in normal keratinization and desquamation, trans epidermal water loss increases, which can cause irritation of the follicular epithelium. The other metabolic by products generated by p. acnes don't help the situation either....

Share this post


Link to post
Share on other sites

This is indeed great info, finding stuff like this on the net is difficult to say the least and i wholly believe this area of knowledge is the key to understanding and curing acne

I have a few questions of my own for anyone interested.

If the localised deficiency of linoleic acid is caused by over-production of sebum as apposed to some form of malfunction then is it not possible to just compensate by consuming higher levels of linoleic acid or the required precursors?

Not necessarily. Acne is often seen even when there isn't a dietary deficency of linoleic acid. Consuming more linoleic acid dosen't necessarily mean that the sebocytes will produce sebum that had a higher concentration of linoleic acid over oleic acid. It seems that high rates of sebum production per sebocyte results in low levels of linoleic acid in the sebaceous esters and triglycerides. I'm not exactly sure as to why though......I need to look into it more.....

Although topical application of linoleic acid seems to stregnthen the epidermal barrier and reduces the size of and formation of comedos (studies vary in the effectiveness).

Also no-one responded to my last post :boohoo: so can anyone give me a reason why oral or topical conjugulated linoleic acid in a FFA form wouldn’t help to achieve this compensatation?

Is CLA too different to linolate / linoleic acid?

CLA is a mixture of linoleic acid and isomers of linoleic acid. CLA is a group of positional and geometric isomers of linoleic acid having a conjugated double-bond system starting at carbon 9, 10, or 11.

These isomers do not have the same stereochemical configuration as linoleic acid does. The exact locations of the double bonds are important to the way they are incorperated into the epidermal ceramides. This is why topical application and oral injestion of CLA doesn't have the same effect as topically applied or injested linoleic acid.

Share this post


Link to post
Share on other sites

So how can we use this information practically?

Possibly by incoporating an agent that supresses sebum production (by actual in vivo alpha-5 reductase inhibition) and linoleic acid (at an adequate concentration) into a simple moisturizer......

I'm not too sure about the practical applications of it. There are still so many holes that need to be filled in. I think a cure to acne will only be achieved by understanding the exact cause if it......

This is the acne research board.....we occasionally just post about random acne research

Share this post


Link to post
Share on other sites

Possibly by incoporating an agent that supresses sebum production (by actual in vivo alpha-5 reductase inhibition) and linoleic acid (at an adequate concentration) into a simple moisturizer......

LabGirl, do you have any thoughts or speculation about why MK386 failed to help acne in that recent study?

Bryan

Share this post


Link to post
Share on other sites

Possibly by incoporating an agent that supresses sebum production (by actual in vivo alpha-5 reductase inhibition) and linoleic acid (at an adequate concentration) into a simple moisturizer......

LabGirl, do you have any thoughts or speculation about why MK386 failed to help acne in that recent study?

Bryan

Bryan can you point me to that study please. If legit, it would certainly contradict the marketing efforts of a number of acne-product companies out there... and i think the literature often cites 5-alpha reductase inhibition as lowering sebum production.

LabGirl, thanks for clarifying the linoleate/linoleic acid thing... i've taken a buttload of chemistry courses and probably should have known that... but i hate chemistry, lol!... i mean its cool on the surface, but all the nomencalture, and learning all the diff reactions in ochem was a pain... Yeah, your're probably better off finding a research opportunity nearby... im sure it was nice to get that offer though. i dont think i could stand working in a lab all day so kudos to all the researchers out there.

This is the acne research board.....we occasionally just post about random acne research

hehe, we're just a bunch of acne geeks.

If the localised deficiency of linoleic acid is caused by over-production of sebum as apposed to some form of malfunction then is it not possible to just compensate by consuming higher levels of linoleic acid or the required precursors?

DrNick, this would be a great hypothesis for a study... and maybe there has already been a study on this... or atleast an epidemiological study on fatty acid intake and acne.

You would also have to consider omega ratios and all that jive to make sure the increased linoleic is actually used by the body.

Share this post


Link to post
Share on other sites

LabGirl, do you have any thoughts or speculation about why MK386 failed to help acne in that recent study?

Bryan can you point me to that study please. If legit, it would certainly contradict the marketing efforts of a number of acne-product companies out there... and i think the literature often cites 5-alpha reductase inhibition as lowering sebum production.

The abstract is below. Yes, the results are quite puzzling. One would _think_ that a potent, specific inhibitor of 5a-reductase type 1 would produce a noticeable improvement in acne, even after a relatively short 3-month period...

J Am Acad Dermatol. 2004 Mar;50(3):443-7.

"A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris"

Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, Heffernan MP, Hickman JG, Hordinsky M, Jarrett M, Kang S, Lucky A, Peck G, Phillips T, Rapaport M, Roberts J, Savin R, Sawaya ME, Shalita A, Shavin J, Shaw JC, Stein L, Stewart D, Strauss J, Swinehart J, Swinyer L, Thiboutot D, Washenik K, Weinstein G, Whiting D, Pappas F, Sanchez M, Terranella L, Waldstreicher J.

University of Pennsylvania Hospital, 36th and Spruce Streets, Philadelphia, PA 19104, USA.

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.

Share this post


Link to post
Share on other sites

The abstract is below. Yes, the results are quite puzzling. One would _think_ that a potent, specific inhibitor of 5a-reductase type 1 would produce a noticeable improvement in acne, even after a relatively short 3-month period...

sorry, i havent had much time to look at this stuff...

bryan, im guessing you already saw this initial study on MK-386:

http://jcem.endojournals.org/cgi/content/full/82/5/1373

they found that "In conclusion, MK-386 is a selective 5R1 inhibitor in man and is associated with a substantial suppression of sebum DHT without an influence on semen DHT".

but the abstract you posted doesnt mention MK-386 so are you sure they used this drug in the study? (for some reason i couldnt get access to the full text through my school)

in any case, it doesnt surprise me that the 5a-reductase type 1 inhibitor didnt improve acne. it just points out that acne is multifactorial and is not easily treated with a purified (synthetic?) substance (as all diseases should not be treated with a purified substance). it would be interesting to see if the drug actually lowered sebum production and still didnt improve acne. if it didnt even lower sebum production, that would just highlight the fact that sebum production is influenced by a variety of factors.

im glad you posted the study... its prompted me to start learning more about how androgens affect acne, and sebum production.

Share this post


Link to post
Share on other sites

If the localised deficiency of linoleic acid is caused by over-production of sebum as apposed to some form of malfunction then is it not possible to just compensate by consuming higher levels of linoleic acid or the required precursors?

DrNick, this would be a great hypothesis for a study... and maybe there has already been a study on this... or atleast an epidemiological study on fatty acid intake and acne.

You would also have to consider omega ratios and all that jive to make sure the increased linoleic is actually used by the body.

I think that this localized deficency of linolate occurs not so much due to a dietary defiency but rather because of a displacment of the linoleic acid by the oleic acid in sebum. Lord knows I certaintly get enough linoleic/linolenic acids, in about a 1:1 or 1:2 in my diet and through supplementation....and I still have acne and most likely a decreaced level of linoleate in my epidermis. I have incredibly oily skin (for unknown reasons....most likely because of wacked out hormones), so regardless of how much linoleic acid I consume (usually about 6g-8g a day) because my sebocytes produce sebum that is much richer in oleic acid than linoleic acid (I'd love to know exactly why....I have more reading to do)....

I'm also looking into oxidative stress as a secondary cause of this linoleate delocalization......

Share this post


Link to post
Share on other sites

bryan, im guessing you already saw this initial study on MK-386:

http://jcem.endojournals.org/cgi/content/full/82/5/1373

Yes, I've read the abstract before, but not the whole thing. Thanks for providing that link to the whole study!

but the abstract you posted doesnt mention MK-386 so are you sure they used this drug in the study? (for some reason i couldnt get access to the full text through my school)

They refer to it by a different name in the acne study, but because of little things they say about it here and there and because of the references they cite, I'm almost POSITIVE that it really is MK386 which they used. I'd say I'm about 95% sure of it.

in any case, it doesnt surprise me that the 5a-reductase type 1 inhibitor didnt improve acne. it just points out that acne is multifactorial and is not easily treated with a purified (synthetic?) substance (as all diseases should not be treated with a purified substance).

Perhaps, but one would expect at least SOME benefit from such a therapy, even if it's just a small one. I still wonder if three months is really a long-enough period of time for such an evaluation.

it would be interesting to see if the drug actually lowered sebum production and still didnt improve acne.

Absolutely! And THAT is what I want them to test! But they didn't measure sebum production at all in that study; the only end-point was the effect on acne itself.

It frustrates me immensely that even though Avodart (dutasteride) has been out now for about three years, I'm still waiting for it to be tested for its effect on sebum production. I can't understand why that hasn't yet been done (as far as I know).

if it didnt even lower sebum production, that would just highlight the fact that sebum production is influenced by a variety of factors.

Indeed.

Bryan

Share this post


Link to post
Share on other sites

I have tried both Finasteride and Dutasteride on multiple occasions and I got an increase in acne in every instance. I should mention that I really don't have acne, generally, other than oily skin (mildly oily), and the aforementioned drugs increased oil production, and consequently, actual break-outs! Through personal experience, I have found that drugs that act as Androgen receptor antagonists (Spironolactone and Fluridil) dry me out very easily.

Share this post


Link to post
Share on other sites

So how can we use this information practically?

Possibly by incoporating an agent that supresses sebum production (by actual in vivo alpha-5 reductase inhibition) and linoleic acid (at an adequate concentration) into a simple moisturizer......

I can't resist relating a little personal anecdote of my own on this issue! :)

What's interesting about your statement above is that linoleic acid itself is likely to be a 5a-reductase inhibitor when applied topically. There are both in vitro and in vivo experiments supporting that idea. And my intention is to test that myself! Recently I started applying a small amount of pure linoleic acid (a couple of drops) to a specific oily area on one side of my face. I planned on doing that for at least a couple of weeks or so, and then using Sebutape test-strips to measure sebum production in that area, compared to the symmetrical (untreated) spot on the opposite side of my face. But I ran into a hitch after just a few days of doing that: the patch of skin to which I was applying the fatty acid started to get "puffy" or swollen-looking, so I was forced to stop the application. The puffiness went away after a while, with no apparent permanent damage.

I tested it later on a second part of my face which I figured was probably less sensitive, and I didn't see any reappearance of the puffiness. Unfortunately, I had to temporarily stop the second test shortly after it began, for other unrelated reasons. But during that short period of time, it appeared to me that sebum production did in fact seem to be noticeably reduced. I'll be able to complete the test much more rigorously in the near future.

Bryan

Share this post


Link to post
Share on other sites

Join the conversation

You can post now and register later. If you have an account, sign in now to post with your account.

Guest
Reply to this topic...

×   Pasted as rich text.   Paste as plain text instead

  Only 75 emoji are allowed.

×   Your link has been automatically embedded.   Display as a link instead

×   Your previous content has been restored.   Clear editor

×   You cannot paste images directly. Upload or insert images from URL.


  • Personalized Advice Quiz - All of Acne.org in just a few minutes


×