Free Fatty Acids

Sebum contains numerous fatty acids and many are quite unique in structure, including a wide variety of straight, branched, saturated, and unsaturated fatty acids (77). In human sebum, about 27% of fatty acids chains are saturated, with the greatest proportion being unsaturated (68%). The vast majority of these are monounsaturated (64%) and about 4% are diunsaturated, with the remainder being composed of fatty acid chains longer than 22 carbons (78). Monounsaturated fatty acids of sebum have a double bond usually inserted at position A9. However, in human sebum there is an unusual placing of the double bond at A6 to produce sapienic acid. Sapienic acid is a very abundant and important monounsaturated fatty acid with 16-carbons and a cis double bond located at the sixth carbon from the carboxyl terminal. This fatty acid has been implicated in acne and is produced by an enzyme unique to sebaceous glands, the A6 desaturase, which has recently been isolated from human skin, and its expression is demonstrated in human sebaceous glands (79). This is the first time that a sebaceous gland-specific functional marker has been demonstrated.

In mice, a similar enzyme has been located in sebaceous glands producing unsaturation between carbons 9 and 10, in other words, a A9 desaturase. Loss of expression of this enzyme in mice results in profound effects with hypoplastic sebaceous glands and an asebic phenotype (80). Although the reason for the presence of these unique fatty acids is not understood, it is speculated that they may impart fluidity on the sebum allowing it to reach the skin surface. An area of active interest is, whether subtle changes in these lipids occur causing blockage in the duct leading to skin diseases such as acne (81) or not. The ratio of A6:A9 fatty acids depends on the rate of sebum secretion—in prepubertal children, and in sebum from the vernix caeosa, as well as elderly individuals the A9 fatty acid predominates. The A6 form is found most commonly in sebum from adults and increases concomittantly with sebum excretion rate. This is thought to be due to a higher level of the A6 desaturase enzyme located in differentiating sebocytes, compared to the enzyme responsible for producing the D9 unsaturated fatty acids, which predominates in undifferentiated sebocytes (82). Thus, as sebum secretion increases, the D6 fatty acid increases and dilutes the D9 fraction. Since high levels of sebum production are implicated in acne, the increased content of sapienate may be relevant to the pathogenesis of this disease.

Diunsaturated fatty acids in sebum have double bonds at positions D5 and D8 or at positions D7 and D10. The major form of dienoic acid was identified as 18:2 D5:8 and named sebaleic acid. This is presumably synthesized by action of the D6 desaturase on palmitic acid (16:0) to produce 16:1 D6, which then undergoes further desaturation at the 5,6 position following chain elongation to 18 carbons (83). Sebaleic acid is thought to be a major component of sebaceous membrane phospholipids and this may explain the increased levels associated with increased rates of sebum excretion and acne. Another important dienoic acid of sebum is linoleic acid (18:2 D9,12), and the levels are inversely related to sebum excretion, with lower levels being found in subjects with high sebum excretion rates (84). As the cells enlarge during differentiation, they may need additional diunsaturated fatty acids for membrane synthesis and presumably synthesize sebaleic acid as a subsititute for linoleic acid, thus explaining the change in ratio of these fatty acids accompanying high sebum excretion (81). There is evidence that linoleic acid from sebum is incorporated into epidermal acylceramides, but when levels of sebum are low it is replaced by sapienic acid, and this could impair barrier function.

There is evidence to suggest that the types of fatty acids synthesized by individuals is controlled by genotype (85) and is unchanged by fluctuations in diet or metabolism. Site to site variations in free fatty acids in skin surface lipids have also been reported (86). It is important to note that the types of fatty acids synthesized seem to vary significantly during the life of an individual: there are several reported examples of this. In addition to those mentioned earlier, a similar effect is seen with some branched chain fatty acids (82). Although human fatty acids are predominantly straight chain, branched chain components were detected with gas chromatography, and saturated fatty acids of human sebum were found to contain methyl branches on one or more of the even numbered carbon atoms throughout the chain (87). The terminally isobranched 15 and 17 carbon species, often comprising wax esters, occur in higher proportions in the sebum of young children, when sebum secretion is low, and in lower quantities in adult sebum (88).

Another enzyme involved in fatty acid synthesis is acetyl CoA carboxylase and this controls the rate-limiting step of this biosynthetic pathway. It exists in different isoforms, but it is not known whether any of these forms predominates in sebo-cytes. These cells incorporate fatty acids into triglycerides and wax esters. Palmitate, palmitoleate, stearate, and oleate seem to be the main fatty acids used for further esterification in the gland (89). Of all the fatty acids investigated, linoleic acid was unique, since it was preferentially broken down to 2-carbon units to fuel further fatty acid synthesis, such as palmitic and oleic acids, and squalene synthesis.

The processes of lipid biosynthesis and terminal differentiation in human sebocytes are quite well understood, but the pathways that control holocrine secretion are still unknown. Immortalized humans (SZ95) sebocytes were found to exhibit DNA fragmentation after a six-hours culture followed by increased lactate dehydrogenase release after 24 hours, indicating cell damage, indicating at least in culture this cell line that lipid release is accompanied by apoptosis (90).

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