A potent oral inhibitor of acetyl-coenzyme-A carboxylase approximately halved the production of facial sebum, most of which arises from de novo lipogenesis, researchers reported.
The production of sebum triglycerides, wax esters, and free fatty acids all depend on local flux through this de novo lipogenesis (DNL) pathway in sebocytes, explained William P. Esler, PhD, and associates. Oral treatment with the investigational agent PF-05175157, a potent inhibitor of acetyl-coenzyme-A carboxylase (ACC) 1 and 2, reduced levels of these sebum components by about 66%, but did not affect levels of compounds that do not depend on the DNL pathway. The results of their mechanistic studies “identify sebocyte DNL as a pathway of importance in the biology of human skin and in the pathogenesis of acne vulgaris,” the researchers wrote in Science Translational Medicine. “Moreover, the observed dependence of human sebum production on local DNL flux and the effectiveness of DNL inhibition by an
Sebum helps moisturize and protect human skin, but increased production is linked to acne vulgaris severity. While sebaceous glands contain ACC and undergo DNL, the role of this pathway in sebum production relative to the recycling of circulating lipids was unknown. For the study, Dr. Esler of Pfizer Global Research and Development in Cambridge, Mass., and associates administered heavy water to 22 healthy volunteers to measure how much stable isotope was incorporated into newly synthesized fatty acids in sebocytes. They found that most skin sebum originated from local flux through the DNL pathway, including 80% of sebum palmitate and more than 80% of sebum sapienate. Furthermore, compared with 10 individuals with acne-free skin, 9 patients with acne vulgaris had about 20% greater sebum production and DNL pathway flux.
Oral therapy for 2 weeks with the ACC inhibitor (200 mg twice daily) was well tolerated and reduced baseline sebum production by 49% when administered to 10 healthy volunteers, the investigators wrote. This effect was not observed in a small placebo comparator group. Importantly, studies of hamsters and guinea pigs failed to implicate the DNL pathway in sebum production, even though these animals have been widely used to model sebum production in humans.
The researchers recommended studying the effects of ACC inhibition in patients with acne vulgaris, the effects of topical ACC inhibition on sebum production, and whether DNL pathway inhibition reduces the number and severity of acne lesions.
Pfizer provided funding; Dr. Esler and 12 coinvestigators are Pfizer employees and stockholders. Two additional coinvestigators are former Pfizer employees while three are current or prior scientific consultants for Pfizer.
SOURCE: Esler WP et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aau8465.