Diet and Acne
9.2 Could Certain Essential Nutrients Affect Acne?
It is obvious that Hippocrates’ ancient but wise statement should hold some truth when applied to acne, given that the most efficacious current therapies for acne are retinoids. Oral administration of isotretinoin (13-cis-retinoic acid, or Accutane) and topical application of its isomers and natural retinoids (e.g. tretinoin) are used as anti-acne therapies (Webster et al. 2009; Berger et al. 2007). 13-cis-retinoic acid (RA) is the only drug that targets all four pathogenic factors of acne and is the most efficient so far in regard to sebum suppression (Katsambas and Dessinioti 2008).
13-cis-RA is a retinoid that potentially derives from the metabolism of vitamin A.
Although several websites state that it is found in small quantities naturally in the body without citing a reference (Vahlquist 1999), we know that at least the natural isomers of RA also affect the disease. With that in mind, we can undoubtedly predict an association between diet and acne.
Vitamin A is essential for skin’s health. Vitamin A deficiency causes abnormal visual adaptation to darkness (night blindness) but also dramatically affects cutaneous biology.
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Dry skin, dry hair, and broken fingernails are among the first manifestations of vitamin A deficiency (Russell 2001). This nutrient, which is stored in the liver, is found also in the skin, particularly in the sebaceous glands, which express retinoid receptors (Orfanos et al. 1997; Tsukada et al. 2000). Let us also not forget that most dermatologists nowadays recommend ingestion of isotretinoin with fatty foods. This recommendation stems from nutritional studies on carotenoids. Retinol (vitamin A), carotenoids (provitamin A), and subsequently retinoids (vitamin A metabolites) are absorbed better with parallel intake of vegetable oils (Fielding et al.
2005; Unlu et al. 2005; Brown et al. 2004; Harrison 2005; Mulokozi et al. 2004;
Ribaya-Mercado 2002).
Therefore, how could the possibility that diet has no effect on acne could be ruled out, especially when diet influences the absorbance of a nutrient, its metabolites, and a drug that affects mitigation of that disease? Maybe acne cannot be cured with nutri- tion, but diet could certainly influence the status of the disease. Perhaps food does not cause or eradicate the disease, but certainly it could ameliorate or worsen its severity.
Let us also consider that lipophilic vitamins A and D have an important impact on keratinocyte biology, which can be crucial to their proliferation in acne. The suscep- tibility of keratinocytes to the antiproliferative effects of vitamins A and D has been documented (Popadic et al. 2008). In vitro studies have shown that RA inhibits pro- liferation of mouse and human keratinocytes via a peroxisome proliferator-activated receptor (PPAR) independent mechanism (Borland et al. 2008). Another report dem- onstrated that all-trans RA, an isoform of RA, increased aquaporin-3 expression and enhanced its biological activity in human skin (Bellemère et al. 2008).
Vitamins A and D are the initial group of nutrients that have been reported to exhibit properties of skin hormones (Reichrath et al. 2007). They control metabolism, inactivation, activation, and elimination of specialized skin cells. Many retinoids are also hormones as they bind to and activate specific nuclear receptors, affecting their function. Vitamin A and its natural metabolites have been approved for topical and systemic treatment of mild, moderate, and severe, recalcitrant acne, as well as photoaging, biological skin aging, acute promyelocytic leukemia, and Kaposi’s sarcoma (Reichrath et al. 2007). Vitamin D’s critical importance for the skin and consequently the body’s endocrine system is demonstrated by the fact that the skin is the site where active vitamin D metabolites, such as 1,25(OH)2D3, are syn- thesized. In keratinocytes, 1,25(OH)2D3 regulates growth and differentiation; and for this reason vitamin D analogues have been developed for the treatment of psoriasis, an aggressive hyperproliferative skin disease. In addition vitamin D analogues are reported to affect the immune system and to offer protection against cancer and autoimmune and infectious diseases in various organs and tissues (Reichrath et al.
2007). All the above examples are cited to reiterate the fact that these nutrients and their metabolites could influence skin hydration, hyperproliferation, and metabolism.
In addition to vitamins A and D, reports have proven that the other major lipo- philic vitamin, E, is delivered onto the skin via sebaceous gland activity (Thiele et al. 1999; Ekanayake-Mudiyanselage et al. 2004). Such sebaceous delivery could make a difference in inflammatory acne because lipid oxidation could increase the inflammation status of the disease. Antinflammatory compounds such as zileuton,
134 A. Pappas
which targets certain enzymes of the lipid oxidation pathways, have been shown to reduce inflammatory lesion counts and sebum production (Zouboulis et al. 2003, 2005). These pathways involve metabolites of polyunsaturated fatty acids (PUFAs).
There are also two fatty acids in our body that are essential and cannot be synthe- sized by human cells: linoleic acid (18:2, D9,12) and linolenic acid (18:2, D9,12,15) (LA). These are important nutrients that need to be obtained from the diet, which is why they are referred to as essential fatty acids. These two essential nutrients are precursors to the omega-6 and omega-3 fatty acid families, respectively, a family of metabolites that are involved in numerous important physiological processes, including inflammation. Consequently we could safely assume that the absence of these important nutrients from our diet could have important implications for both acne and our overall health. Numerous studies have revealed that clinical imbalances of specific essential fatty acids are associated with a variety of skin problems, such as dry, itchy, scaly skin, which is a hallmark sign of fatty acid deficiency (Horrobin 1989). More relevant to this is a publication that suggested that the sebum of acne patients is relatively deficient in linoleic acid (Downing et al. 1986).
The exact fate of these essential nutrients in human sebaceous cells is not yet entirely elucidated. An experimental study (Pappas et al. 2002) unveiled a unique metabolic fate of linoleic acid in sebaceous cells, which is preferentially b-oxidized, contrary to the other predominant fatty acids, which are incorporated to the most common sebaceous lipids. That rapid oxidation and degradation in sebaceous cells allows palmitic acid to be available as the sole substrate to the d6 desaturase of sebaceous cells, which is the predominant desaturase of human sebaceous cells (Ge et al. 2003). That enzyme usually catalyzes the synthesis of more omega-6 derivatives from linoleic acid, since it is the enzyme’s preferred substrate. There is also considerable evidence that linoleic acid is an essential structural component of skin ceramides, important for barrier function.
Sebum analysis demonstrates that these essential fatty acids and their derivatives comprise small amounts of surface lipids (Nicolaides 1974). However, two intriguing studies (Fu and Sinclair 2000; Fu et al. 2001) revealed a firm association of these two fatty acids and the skin. When guinea pigs consumed radioactively labeled linoleic and a-LA, the lipids in skin and fur were predominantly labeled.
Following the administration of 14C-labeled aLA, 46% of the radioactivity was associated with the skin and fur lipids; and about 39% of the label was not recovered in the body lipids and was assumed to have been expired as CO2 or unabsorbed.
These data identify a new route of metabolism of aLA in these species and presumably through the sebaceous glands onto fur lipids and subsequently skin. Perhaps in humans the distribution could be different, but at least the above study revealed that these essential nutrients could enter from the diet, survive the digestive tract, and reach the skin’s surface unaltered. A recent nutritional clinical study (De Spirt et al.
2009) in two groups of women who consumed flaxseed or borage oil for 12 weeks revealed that the daily ingestion of 2.2 g aLA or 2.2 g linoleic and g-linolenic acid, respectively, demonstrated skin benefits. Skin irritation, changes in skin red- dening, and blood flow were diminished in both groups compared to the placebo group, providing evidence that skin properties can be modulated by intervention with dietary fatty acids.
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Another class of nutrients that derives from the diet includes minerals such as zinc, copper, selenium, and iron, which known to influence antiinflammatory and proinflammatory enzymes (e.g., desaturases and lipoxygenases). Could a diet rich in zinc or selenium bring benefit to a patient with acne? Could a diet rich in iron or copper worsen acne? We simply do not know because the proper nutritional clinical studies have not been performed.