Sunday, March 31, 2013

Skin Lipids

Sebum 

In addition to keeping the skin and hair supple, sebum also has antimicrobial properties.  The sebaceous glands are an important part of the innate immune system and function like an immune organ (they are regulated by things such as corticotrophin releasing hormone and vitamin D) [1].  The sebaceous gland also transports antioxidants in and onto the skin, regulates bacterial populations by having pro and anti-inflammatory functions and is involved in the wound healing process [2]

[3]

People with acne secrete 59% more sebum and the quality of sebum is also different.  The major differences are that people with acne secrete 120% more squalene, 84% more triglycerides and 21% less free fatty acids than controls [4] 

* The wax esters and squalene are unique to sebum and not found elsewhere in the body [3] 

Fatty Acids 

Fatty Acids in Sebum 

Triglycerides and free fatty acids make up about 57.5% of sebum.  Sebum has many of the usual but also some different fatty acids: 

  • Sapienic acid (16:1 cis n-10), which is unique to humans (hence the name).  Delta-6-desaturase converts palmitic acid (16:0) to sapienic acid
  • Sebaleic acid (18:2 cis n-10).  Elongase and desaturase enzymes convert sapienic acid to sebaleic acid [3]

* Humans are also the only animal that has triglycerides in their sebum and the only animal that normally gets acne [5] 

Linoleic Acid

People with acne may have a lower proportion of linoleic acid (LA) in their keratinocytes in the follicle wall. This may be because LA is an essential fatty acid and people with acne produce more sebum, which may dilute LA (sebum excretion is inversely correlated with LA). When sebaceous glands are deficient in LA they synthesise more sabeleic acid as an alternative PUFA. However, this leads to poor epidermal barrier function (remember that the skin is a barrier to the outside world), which can lead to water loss and then keratinocyte hyperproliferation*, pro-inflammatory cytokine release (from keratinocytes into the dermis), and allow P. acnes colonisation through barrier loss and increasing water [3] [5] [6] [7] [8] [9].

LA also inhibits ROS generation by neutrophils [10] and low LA may be a cause of the elevated IL-1 in people with acne, prior to comedone formation [5].

* Impaired water barrier function is also seen in diseases of hyperkeratosis [9] 

SFAs and MUFAs 

People with acne have a lower ratio of 16:0/16:1 ratio in triglycerides and wax esters [3] and from an acne point of view MUFAs aren’t that great for the following reasons: 

  • A higher proportion of MUFAs in sebum is associated with more sebum production and acne lesions, which is consistent with adolescents, who have a higher proportion of sapienic acid, produce more sebum and are more likely to get acne [11]
  • MUFA can alter keratinocyte proliferation and differentiation [2].  Topical application of MUFAs (oleic acid and palmitoleic acid) caused scaly skin, abnormal keratinization and epidermal hyperplasia whereas triglycerides and SFA didn’t have that effect [11]
  • A low glycemic load diet (but also better food quality) increases the SFA:MUFA ratio in sebum and improved acne (see picture below for mechanisms).  An increase in the SFA:MUFA ratio in sebum predicts improvement in acne [11] 

Lauric acid is one the free fatty acids found in sebum.  It has strong antimicrobial activity in vitro against skin bacteria including P. acnes and topical application or intradermal injection of lauric acid reduces inflammation caused by P. acnes and reduces the number of bacteria.  Palmitic acid, oleic acid and sapienic acid [1] also have some antimicrobial properties and increase antimicrobial peptides in sebocytes [2] 

* The SFAs in sebum are mainly palmitic acid while the MUFAs in sebum are mainly sapienic acid and palmitoleic acid.

[11]

Sunday, March 24, 2013

Your Hormones are Going Crazy

The pop explanation for acne is that ‘your hormones are going crazy’.  The two classes of hormones best researched in regards to acne are the androgens and insulin/GH/IGF-1.  There’s another hormone that I think is quite involved in acne but I’ll save it for a few weeks 

Androgens 

Androgens include testosterone, dihydrotestosterone (DHT), DHEA and some of their derivatives.  They are considered ‘male hormones’ because men have higher levels of them and they are responsible for many male secondary sex characteristics. 

Testosterone can be converted to dihydrotestosterone by the enzyme 5α-reductase (5AR).  There are two isozymes (multiple forms of enzymes) of 5AR: type 1 which is active in the sebaceous gland and type 2 which is active in the prostate gland.  There is more activity of type 1 5AR (therefore more DHT) in sebaceous glands in the skin prone to acne (such as the face), which partially explains the acne in those areas.  (DHT seems to promote acne more than testosterone) [1] 

Androgens increase the size and secretion of sebaceous glands.  DHT increases sebum production and the proliferation of sebocytes [2] and testosterone increases proliferation of sebocytes and works with PPARs to increase lipid synthesis [1].  Androgen receptors on keratinocytes and sebocytes promote hyperkeratinisation, sebaceous gland development and sebogenesis (generation of sebum) [3] 

Evidence supporting the role of androgens in acne: 

  • Elevated androgen levels due to androgen-producing tumours, administration of testosterone or DHEAS*, anabolic steroids or PCOS is associated with acne and people with acne have higher DHT [4]
  • Severe acne is often associated with elevated serum androgen levels and females with severe acne have higher DHEAS [3]
  • Those who lack functional androgen receptors and males who are castrated produce no/less sebum and don’t develop acne.  Also a DHT inhibitor improves acne [3] [5]
  • Androgens seem to a major reason why acne usually doesn’t occur prior to adolescence is more prevalent during adolescence.  (Acne prior to adolescence is less inflammatory as there’s insufficient sebum to support as much P. acnes (acne during this time is associated with elevated DHEAS)) [6] 

However, while serum androgens are elevated in severe acne the correlation doesn’t always apply to mild/moderate acne, If androgens are so closely associated with acne then males should have a much higher incidence and greater severity, but don’t and finally, some epidemiological studies find no relationship between androgen levels with the presence and severity of acne in men [6] 

It’s unknown as to whether serum androgens or those made by the skin and sebaceous glands are responsible for acne, as sebaceous glands are capable of synthesising T and DHT from cholesterol and cholesterol from acetate.  An explanation for the inconsistencies above could be that the skin and sebaceous androgens are more relevant or perhaps people prone to acne are more sensitive to androgens (have more receptors). 

* DHEA sulphate (DHEAS) is an adrenal androgen and a metabolite of DHEA.  DHEA is a precursor to testosterone and a weak androgen 

Insulin, Growth Hormone and IGF-1 

Insulin, growth hormone (GH) and IGF-1 have many roles in the body.  Insulin is best known for increasing glucose transport into cells and GH/IGF-1 are best known as growth promoters. 

Insulin increases IGF-1 and lowers IGF-1 binding proteins.  GH is also known as somatotropin, and like other ‘tropins’ GH stimulates production of effector hormones, in this case IGF-1, which then carry out the biological effects. 

Insulin and IGF-1 have other effects that can promote acne, such as stimulating lipogenesis of sebaceous glands, augmenting androgen receptor signalling and increasing free androgens by lowering SHBG (thereby increasing androgen activity).  IGF-1 also increases DHEA sulphate (and is associated with DHEA sulphate levels), increases proliferation of sebocytes (and is associated with the amount of sebum excreted), promotes testosterone production in men and increases 5AR [1] [7] 

Evidence supporting the role of insulin/IGF-1 in acne: 

  • Acromegaly is a disorder of GH hypersecretion and is associated with elevated IGF-1, insulin resistance* and acne [7]
  • Recombinant human IGF-1 increases androgens and acne, which normalises when the dose is reduced and when the treatment is interrupted [7]
  • The number of total acne lesions, inflammatory lesions, serum levels of dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS), each correlated with serum IGF-1 levels in women with acne [7]
  • Retinoic acid (a metabolite of retinol/vitamin A) increases IGF binding protein-3, which inhibits the activity of free IGF-1 and is therapeutic for acne [7]
  • PCOS associated with increased IGF-1 (2x higher), DHEA sulphate, IR, hyperinsulinemia and acne.  Metformin is an insulin sensitiser used to treat PCOS and it reduces androgen levels and improves acne and PCOS symptoms [7]
  • Acne is most prevalent during adolescence (mid adolescence in particular) when GH and IGF-1 are highest [6] 

High glycemic load diets are associated with hyperglycemia, reactive hyperinsulinemia and increased IGF-1.  Low GL diets lower IGF-1 increase IGF-1 binding proteins and significantly improve acne after 12 weeks. [7] 

There are associations between milk and acne (~1.2), especially skim milk (~1.4).  High milk consumption is associated with a 10–20% increase in IGF-1 levels in adults and a 20–30% increase in children.  This is because milk contains active IGF-1** and IGF-2 and dairy proteins (except cheese) are highly insulinogenic*** [7] 

* GH may promote insulin resistance by increasing FFA 

** There are high levels of IGF-1 in milk after pasteurization and homogenization.  Bovine and human IGF-1 also have the same amino acid sequence 

*** I’m surprised these numbers aren’t higher considering all the mechanisms where insulin and IGF-1 promote acne

Sunday, March 17, 2013

Is Acne a Disease?

The Prevalence of Acne 

Acne affects between 40-50 million in the US, which in 1998 was between 14.8-18.5% of the population [1].  Acne is more common during adolescence, but it also affects a smaller proportion of adults (see table) [2] and even about 36% of 4-7 year olds have acne [3] 

Age
Prevalence of Acne
10-12
28-61%
16-18
79-95%
Men
Women
>25
40%
54%
Middle Age
3%
12%

Acne is considered a fairly normal part of adolescence as it is so common at that age, and is one of those things that apparently, just happens. 

Being considered a normal part of adolescence may have led to studies such as the one quoted below, which suggest acne is not a disease, but rather an evolutionarily adaptive, physiological process. 

“…adolescent acne is a normal physiological process - a high-order psychoneuroimmune interaction - that functions to ward off potential mates until the afflicted individual is some years past the age of reproductive maturity, and thus emotionally, intellectually, and physically fit to be a parent.” [4] 

There are two major flaws with that idea: 

1.      Many people who aren’t adolescents have acne (see table)
2.      Hunter-gatherers don’t seem to get acne 

There have been no reports of acne among the Inuit, Okinawans, Aché (hunter-gatherer tribe in Paraguay) and Kitavans.  It’s possible that these people are genetically resistant to acne, but that doesn’t really explain their absence of acne as other South American Indians and Pacific Islanders have acne when they adopt a western lifestyle [3] [5] 

How Acne Happens 

The development of acne seems to have a few key steps: 

1) Hyperkeratinisation of the Hair Follicle 

Dead skin cells in the hair follicle would normally detach (desquamate) and be forced out of the follicle, mainly by the growing hair.  In hyperkeratinisation that process is blocked and many dead skin cells don’t leave the follicle due to an excess of keratin, which is the main protein of skin.  Keratin sticks the dead skin cells together and blocks the hair follicle or the sebaceous duct (where sebum comes from).  When the normal flow of sebum onto the skin surface is obstructed the comedones (blackheads and whiteheads) are formed which starts the process of acne [6] [7]. 

People with acne have abnormal keratinisation that that obstructs the pilosebaceous unit (hair follicle + sebaceous gland + arrector pili muscle (small muscles that cause goosebumps)) [6]. 

2) Androgen-mediated Increases in Sebum Production 

Sebum is an oily substance that consists of triglycerides, wax esters, squalene and sterol (mostly cholesterol) esters.  Sebum is produced by sebocytes in the sebaceous gland and the main function of sebum is to keep the skin and hair supple. 

Acne cannot occur without sebum [7] and people with acne secrete about 2.2 times more sebum [8].  Acne occurs mainly on the face, upper chest and upper back, which are the parts of the body that produce the most sebum [9].  Androgens are largely responsible for sebum production. 

3) Colonization of the Follicle by Propionibacterium acnes (P. acnes) 

P. acnes are commensal anaerobic gram-positive bacteria that live mainly on the skin.  They are normally harmless, but are generally implicated in acne (hence their name) (see the table below) [10] and are pretty strongly associated with acne [9]: 

  • People with acne have more P. acnes
  • P. acnes progressively increases from pre-adolescence to early adulthood 
  • P. acnes correlates with sebum excretion
  • The face, upper chest and upper back have more P. acnes and sebum 
  • P. acnes can induce a T cell reaction
  • Antibiotics are used as a treatment for acne and antibiotic resistance is associated with treatment failure (although may also be due to biofilms and poor penetration of biofilms) 

However, the incidence and severity of doesn’t always correlate with P. acnes, and improving acne doesn’t always reduce P. acnes.  Although this could be because some treatments are anti-inflammatory [9], which may also explain the lack of correlation. 

4) Hyperinflammatory Immune Response

Inflammation is a major part of acne.  Acne patients mount an immune response to P. acnes that is not seen in normal patients [9].  There are several sources of inflammation in acne (also see the table below): 

  • P. acnes generate lipases that can break down the triglycerides in sebum into glycerol and free fatty acids.  FFA (particularly medium chain C8 to C14*) are comedogenic, irritate the follicular lining and can lead to rupture of the follicle with release of the follicular contents into the surrounding dermis, which leads to inflammatory lesions (people with acne also tend to be more sensitive to FFA) [6]. 
  • P. acnes releases pro-inflammatory enzymes and cytokines 
  • P. acnes can bind to toll-like receptors, which initiates an inflammatory response 

* Which may explain how coconut oil and MCT oil can be a trigger for acne in some people.

[10]

So we have four main questions: 

1.      What are the causes of hyperkeratinisation of the hair follicle?
2.      What are the causes of excessive sebum production?
3.      If there is, is there any way to avoid colonisation by P. acnes?
4.      What are the causes of the hyperinflammatory immune response?

Sunday, March 10, 2013

Causes of Inflammation

This isn’t a complete list, but includes several possible causes of chronic inflammation.  Unlike the other posts I changed the reference count to reset at each sub-heading to make this post easier to edit

Autoimmune Diseases, Allergies and Asthma

With autoimmune diseases the immune system attacks the body’s tissues, causing inflammation not only locally, but often systemically as well.  So it’s not surprising then, that inflammatory markers are elevated in people who have autoimmune diseases [1].  People who have an autoimmune disease will likely have a poorly regulated immune system and intestinal permeability, both of which can be inflammatory regardless of autoimmunity and a factor in other diseases as well.  People who have allergies and asthma have an inappropriate immune response to certain stimuli suggesting that they also have a poorly regulated immune system and that the diseases may be a source of chronic inflammation.  See Autoimmune Disease

Chronic Stress / Glucocorticoid Resistance

Glucocorticoids (such as cortisol) have anti-inflammatory effects by suppressing the immune system.  Glucocorticoid resistance (GCR) is where glucocorticoids fail to adequately suppress the HPA axis and the immune system when needed, which results in elevated glucocorticoid levels and a more intense and prolonged inflammatory response.  Glucocorticoid resistance can be caused by inflammatory cytokines and chronic stress [1] [2] [3] and is thought to affect “between 40 and 60% of depressed patients, especially those presenting melancholic and/or psychotic symptoms” [1].

Homocysteine

Homocysteine (Hcy) is formed when methionine donates a methyl group (CH3) (often to DNA in a process called DNA methylation, which regulates whether genes are turned on or off).  Inflammation increases homocysteine [1], and homocysteine increase oxidative stress [2] and ER stress [3], but it can be converted to other molecules through several means: (1) vitamin B6 is a cofactor of an enzymatic reaction that converts homocysteine to cysteine; (2) a metabolite of folate and a vitamin B12 related enzyme can recycle homocysteine back to methionine; and (3) a metabolite of choline (betaine) can donate a methyl group to homocysteine, which converts it back to methionine.  While vitamin B6, B12 and folate shouldn’t be an issue for someone eating a whole food, omnivorous diet it’s unlikely that one would get sufficient choline without regularly consuming eggs, organ meat or a fair bit of either muscle meat of whole wheat.  See my nutrient database.  Also, Chris Masterjohn discusses the importance of glycine to promote glutathione synthesis and avoid excessive methylation.  See Beyond Good and Evil: Synergy and Context With Dietary Nutrients

Insulin Resistance

Insulin resistance (IR) leads to elevated free fatty acids and hyperglycemia, which increases oxidative stress and inflammation.  Insulin resistance can also promote inflammation by reducing insulin signalling in some places and increasing it in others.  For example, insulin increases endothelial nitric oxide synthase (eNOS) and insulin resistance results in lower eNOS [2]; and insulin increases the activity of the RAAS and insulin resistance results in higher RAAS activity from this direct effect [3] but also from elevated FFA activating the sympathetic nervous system and then the RAAS [4].  See What Causes Insulin Resistance? Part VII (and the previous 6 posts), Mitochondrial Dysfunction and Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Part 1 (and Part 3)

Iron Overload

While iron is essential to life and is needed for many important functions, too much iron can be a problem.  Free iron is toxic to cells as hydrogen peroxide (H2O2) can react with iron ions to produce highly reactive hydroxyl radicals (OH-), which is known as the Fenton reaction.  To prevent this from happening we have a protein called ferritin that stores iron.  Blood ferritin levels increase when the body's iron stores increase.  But ferritin is also an acute phase reactant, and increases in response to infections and inflammation because ferritin makes iron unavailable for pathogens, which require iron for growth and proliferation (so high ferritin may not necessarily mean high iron).  Phlebotomy can lower markers of the metabolic syndrome [1].  See Chris Kresser’s AHS 2012 talk for information on the causes, problems, testing and treatment of iron overload

Lipopolysaccharide/Endotoxins

Lipopolysaccharide (LPS) is an endotoxin of gram-negative bacteria that activates the immune system and triggers a strong inflammatory response.  LPS is often used experimentally to cause inflammation and certain diseases in animal models [1] [2].  Other bacterial products and DNA also promote strong inflammatory response.  See Leptin Resistance for now on some causes of elevated LPS from the (I plan to do a series on gut health at some point), but remember that LPS can also come from bacteria in the mouth, and see Is Postprandial LPS From Fats a Cause for Concern?

Mitochondrial Dysfunction

Mitochondria generate most of the ATP our cells use from the macronutrients in food, but also roughly 90% of all endogenous reactive oxygen species (ROS).  ROS are physiological signalling molecules, but in excess they can overwhelm antioxidant defences, leading to oxidative stress and inflammation [1] [2].  See Mitochondrial Dysfunction

Obesity

While obesity can be caused by inflammation, inflammation can also be a consequence of obesity through a few different mechanisms: (1) as the adipocytes fill up they become progressively more insulin resistant, leading to elevated FFA which binds to TLR4 on macrophages and initiates an inflammatory response, causing an increase in pro-inflammatory cytokines, macrophage infiltration in adipocytes, etc [1]; (4) as the abdominal adipocytes (in particular) fill up they may also become hypoxic, which triggers the release of an inflammatory molecule called HIF-1α [2]; and (2) obesity results increases the activity of the RAAS due to increased sympathetic activity from leptin [3] and greater release of angiotensinogen (ACE converts it to angiotensin) from adipocytes [4].  However, some overweight/obese people are insulin sensitive and don’t have chronic inflammation.  See Obesity

Sunday, March 3, 2013

Inflammation

“Inflammation is one of those words that people use without really thinking about its actual meaning” 
-          Mark Sisson 

Which is the whole point of the next two posts. 

The Role of Inflammation in Chronic Disease 

Inflammation is a major cause of chronic diseases such as obesity, osteoporosis, autoimmune diseases, depression, cancer and cardiovascular disease. 

  • Several pro-inflammatory cytokines increase SOCS3 and TNF-α increases PTP1B.  SOCS3 and PTP1B and increase leptin resistance, therefore obesity [1].
  • Several pro-inflammatory cytokines increase osteoclast synthesis and activity and induce osteoblast apoptosis, leading to a higher rate of bone resorption and a lower rate of bone formation, which contributes towards osteoporosis [2].
  • Some pro-inflammatory cytokines are required for Th17 cell development and IL-17 production, which can lead to an elevated Th17:Treg cell (and IL-17:IL10) ratio, which is an immune profile that promotes autoimmune disease [3]
  • Elevated levels of pro-inflammatory cytokines inhibit neurogenesis and initiate apoptosis, which contributes to the hippocampal atrophy seen in depression [4]
  • Pro-inflammatory cytokines promote angiogenesis, growth and proliferation of tumour cells and inhibit apoptosis of tumour cells and NFκB also promotes tumour survival, metastasis and inhibits the adaptive immune system, which promotes cancer [5] 
  • Pro-inflammatory cytokines promote monocyte adhesion to endothelial cells, endothelial dysfunction, oxidative stress and apoptosis of endothelial cells, all of which lead to the development of atherosclerosis and CVD [6]. 

Acute vs. Chronic Inflammation 

But inflammation can also be a good thing: 

  • Inflammation is a response by the innate immune system to pathogens, damaged cells or irritants
  • Inflammation initiates the healing response
  • Inflammation is necessary to get the physiological adaptations from exercise 

The inflammation from bruises, cuts, burns, exercise, etc, is acute inflammation, which only lasts a short time and is a normal and adaptive physiological response.  The inflammation from something like metabolic endotoxemia and autoimmune diseases, etc, is chronic inflammation, which generally lasts a long time (until the cause is resolved) and may not necessarily be adaptive.  It’s the chronic inflammation* that promotes disease** and should concern us. 

* When I say ‘inflammation’ that’s usually just shorthand for ‘chronic inflammation’.  It would be silly to suggest exercise or a few bruises promote chronic disease. 

** While acute inflammation can be a trigger for chronic disease, it’s likely that this will only the case for people who don’t resolve inflammation well, which could be due to them having low Treg cells/IL-10 or glucocorticoid resistance, etc. 

If you want to read about the basics of inflammation see What is Inflammation? and What’s All This Talk About Inflammation?.  Mark Sisson explains it well and there’s no need for me to repeat what he says.  You can also read the Wikipedia article on inflammation 

Rather than finish up with ‘chronic inflammation is bad’, the next post will be a list of some causes of chronic inflammation and what to do about it.