The contribution of de novo lipogenesis to lipid synthesis in sebum in healthy volunteers

Skin is a metabolically active tissue and contains sebaceous glands which synthesize sebum. Sebum is a complex lipid mixture that is excreted on the skin surface and consists of of triacylglycerols, diacylglycerols, free fatty acids (which together account for 50–60% of its composition), wax esters (20–30%), squalene (10–16%), and cholesterol esters (2–4%). Acne is a skin disorder with multifactorial pathogenesis and sebum production is considered one of the main contributors. However, the metabolic pathways regulating human sebum lipid composition and production are not well understood. The goal of this study was to determine the contribution of de novo fatty acid synthesis (DNL) to sebum production in healthy humans utilizing heavy water labelling and mass isotopomer distribution analysis (MIDA). Female and male volunteers were recruited by advertisement (18–35 years). Subjects received loading doses of 2 H 2 O totaling 480 mL of 70% 2 H 2 O, divided into 8 doses of 60 mL each and subjects continued to take a daily oral 2 H 2 O dose (60 ml of 70% 2 H 2 O) until Day 21. Subjects returned for outpatient visits on days 0, 2, 4, 7, 11, 14 and 21. At all outpatient visits, plasma samples were collected to determine body water 2 H 2 O. Sebum samples were also collected using Sebu‐Test Strip (CuDerm Corp., Dallas TX) from both cheeks and forehead for the measurement of DNL. Saliva sample were collected at home on Day 1 and 3 for body water 2 H 2 O enrichment. Total lipids were extracted with hexane from sebum samples. Total fatty acids were then trans‐esterified to fatty acid methyl esters, in preparation for gas chromatographic/mass spectrometric (GC/MS) analysis. The proportion of tissue palmitate derived from DNL (i.e., made “new” from acetyl‐CoA precursors) was calculated by MIDA, as described previously. The body water enrichments were stable and on average 0.98 ± 0.37% (n=10, Days 2 through 21). Fractional DNL contribution to sebum palmitate rose to an average (SD) of 83.6 % (24%) in forehead sebum, 83.5 % (18%) in left cheek sebum and 82.7 % (18%) in right cheek sebum after 21 days of 2 H 2 O labeling (n=10 subjects). DNL contribution to total palmitate was similar in sebum collected from the three different collection sites. Sapeinic acid, a non‐essential fatty acid exclusive to sebum, showed a similar contribution from DNL, ruling out contribution to palmitate from non‐sebocyte sources as the explanation for high DNL contribution.. The fractional replacement rate of newly synthesized palmitate in sebum lipids was on average 26 % per day, which translates into a half life of 3 days and an average plateau of 87 % (n=10 subjects, n=3 collection sites). No significant differences between collection sites were observed for any kinetic parameter. Contribution of DNL to sebum palmitate was significantly greater compared to the contribution of DNL to VLDL‐TG palmitate (~23%), indicating that sebum palmitate is mostly synthesized within the sebaceous gland rather than imported from blood lipoproteins. Conclusions the main source of sebum palmitate is DNL in healthy subjects; sebum palmitate is locally synthesized in the sebaceous gland; the replacement rate of sebum palmitate is 27% per day. These findings suggest than local modulation of DNL in sebocytes is important in oil production in skin and inhibition of local DNL may represent a therapeutic target in acne. Support or Funding Information KineMed, Inc. Pfizer Inc.