Research ArticleACNE VULGARIS

Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition

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Science Translational Medicine  15 May 2019:
Vol. 11, Issue 492, eaau8465
DOI: 10.1126/scitranslmed.aau8465

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Getting the skinny on sebum

Sebum, an oily material secreted by glands in the skin, has a physiological role, but abnormally high secretion of sebum can be associated with acne. Through a detailed investigation of sebum production in human skin samples and volunteer individuals, Esler et al. determined that most of the sebum in human skin is generated through de novo lipogenesis rather than recycled from circulating lipids. With this knowledge, the authors designed an inhibitor of acetyl-CoA carboxylase, a key enzyme in de novo lipogenesis, and tested it in cells, in rats, and in humans. This compound was well tolerated and successfully suppressed sebum production in human individuals.

Abstract

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de novo lipogenesis (DNL) pathway within the sebocyte. About 80 to 85% of sebum palmitate (16:0) and sapienate (16:1n10) were derived from DNL, based on stable isotope labeling, much higher than the contribution of DNL to triglyceride palmitate in circulation (~20%), indicating a minor contribution by nonskin sources to sebum lipids. This dependence on local sebocyte DNL was not recapitulated in two widely used animal models of sebum production, Syrian hamsters and Göttingen minipigs. Confirming the importance of DNL for human sebum production, an acetyl-CoA carboxylase inhibitor, ACCi-1, dose-dependently suppressed DNL and blocked synthesis of fatty acids, triglycerides, and wax esters but not free sterols in human sebocytes in vitro. ACCi-1 dose-dependently suppressed facial sebum excretion by ~50% (placebo adjusted) in human individuals dosed orally for 2 weeks. Sebum triglycerides, wax esters, and free fatty acids were suppressed by ~66%, whereas non–DNL-dependent lipid species, cholesterol, and squalene were not reduced, confirming selective modulation of DNL-dependent lipids. Last, individuals with acne vulgaris exhibited increased sebum production rates relative to individuals with normal skin, with >80% of palmitate and sapienate derived from DNL. These findings highlight the importance of local sebocyte DNL for human skin sebaceous gland biology and illuminate a potentially exploitable therapeutic target for the treatment of acne vulgaris.

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