Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil

David W. Hunt, Geoffrey C. Winters, Roger W. Brownsey, Jerzy E. Kulpa, Kathryn L. Gilliland, Diane Thiboutot, Hans E. Hofland

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes. TrueMass Sebum Panel analyses showed a reduction in saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in OG-treated sebocytes. There was no shift to shorter acyl chain lengths observed, suggesting that the fatty acid chain elongation process was not affected. OG is a pro-drug of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid and was designed to enhance delivery in vivo. Topical application of OG but not 5-(tetradecyloxy)-2-furoic acid significantly reduced hamster ear sebaceous gland size, indicating that this pro-drug approach was critical to obtain the desired activity in vivo. High-performance liquid chromatography analyses of hamster ear extracts showed that OG treatment increased ACC levels and the ratio of acetyl-CoA to free CoA in these animals, indicating increased fatty acid oxidation. These changes are consistent with ACC inhibition. Matrix-assisted laser desorption/ionization imaging showed that OG applied onto Yorkshire pig ears accumulated in sebaceous glands relative to the surrounding dermis. Sebaceous gland ACC represents an attractive therapeutic target given its central role in formation of sebum, a key factor in acne pathogenesis.

Original languageEnglish (US)
Pages (from-to)1415-1423
Number of pages9
JournalJournal of Investigative Dermatology
Volume137
Issue number7
DOIs
StatePublished - Jul 1 2017

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Sebum
Acetyl-CoA Carboxylase
Sebaceous Glands
Fatty Acids
Ear
Prodrugs
Cricetinae
Lipids
Acetyl Coenzyme A
Cholesterol Esters
Waxes
Diglycerides
Biosynthesis
Acne Vulgaris
High performance liquid chromatography
Coenzyme A
Dermis
Chain length
Ionization
Elongation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Hunt, David W. ; Winters, Geoffrey C. ; Brownsey, Roger W. ; Kulpa, Jerzy E. ; Gilliland, Kathryn L. ; Thiboutot, Diane ; Hofland, Hans E. / Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil. In: Journal of Investigative Dermatology. 2017 ; Vol. 137, No. 7. pp. 1415-1423.
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Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil. / Hunt, David W.; Winters, Geoffrey C.; Brownsey, Roger W.; Kulpa, Jerzy E.; Gilliland, Kathryn L.; Thiboutot, Diane; Hofland, Hans E.

In: Journal of Investigative Dermatology, Vol. 137, No. 7, 01.07.2017, p. 1415-1423.

Research output: Contribution to journalArticle

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AU - Hunt, David W.

AU - Winters, Geoffrey C.

AU - Brownsey, Roger W.

AU - Kulpa, Jerzy E.

AU - Gilliland, Kathryn L.

AU - Thiboutot, Diane

AU - Hofland, Hans E.

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N2 - Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes. TrueMass Sebum Panel analyses showed a reduction in saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in OG-treated sebocytes. There was no shift to shorter acyl chain lengths observed, suggesting that the fatty acid chain elongation process was not affected. OG is a pro-drug of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid and was designed to enhance delivery in vivo. Topical application of OG but not 5-(tetradecyloxy)-2-furoic acid significantly reduced hamster ear sebaceous gland size, indicating that this pro-drug approach was critical to obtain the desired activity in vivo. High-performance liquid chromatography analyses of hamster ear extracts showed that OG treatment increased ACC levels and the ratio of acetyl-CoA to free CoA in these animals, indicating increased fatty acid oxidation. These changes are consistent with ACC inhibition. Matrix-assisted laser desorption/ionization imaging showed that OG applied onto Yorkshire pig ears accumulated in sebaceous glands relative to the surrounding dermis. Sebaceous gland ACC represents an attractive therapeutic target given its central role in formation of sebum, a key factor in acne pathogenesis.

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