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Olumacostat Glasaretil, a Promising Topical Sebum-Suppressing Agent that Affects All Major Pathogenic Factors of Acne Vulgaris

2017; Elsevier BV; Volume: 137; Issue: 7 Linguagem: Inglês

10.1016/j.jid.2017.01.026

1523-1747

Bodo C. Melnik,

Dermatology and Skin Diseases

Hunt et al. show that olumacostat glasaretil, an inhibitor of acetyl coenzyme A carboxylase, reduces saturated and monounsaturated fatty acyl chains in sebaceous lipids. Topical olumacostat glasaretil application decreases hamster ear sebaceous gland size and shows efficacy in treating patients with acne vulgaris. Olumacostat glasaretil-mediated sebum suppression may reduce Propionibacterium acnes growth and biofilm formation, comedogenesis, and inflammation. Hunt et al. show that olumacostat glasaretil, an inhibitor of acetyl coenzyme A carboxylase, reduces saturated and monounsaturated fatty acyl chains in sebaceous lipids. Topical olumacostat glasaretil application decreases hamster ear sebaceous gland size and shows efficacy in treating patients with acne vulgaris. Olumacostat glasaretil-mediated sebum suppression may reduce Propionibacterium acnes growth and biofilm formation, comedogenesis, and inflammation. Clinical Implications•Topical olumacostat glasaretil (OG), a prodrug inhibitor of acetyl coenzyme A carboxylase, is a promising novel sebum suppressing agent for the treatment of acne vulgaris.•OG treatment reduces sebaceous lipogenesis, production of saturated and monounsaturated acyl chains of major sebaceous lipids, and sebaceous gland size.•OG improves features of “acne sebum” that are involved in Propionibacterium acnes growth, P. acnes biofilm formation, comedogenesis and sebofollicular inflammation. •Topical olumacostat glasaretil (OG), a prodrug inhibitor of acetyl coenzyme A carboxylase, is a promising novel sebum suppressing agent for the treatment of acne vulgaris.•OG treatment reduces sebaceous lipogenesis, production of saturated and monounsaturated acyl chains of major sebaceous lipids, and sebaceous gland size.•OG improves features of “acne sebum” that are involved in Propionibacterium acnes growth, P. acnes biofilm formation, comedogenesis and sebofollicular inflammation. Sebum, the lipid-rich holocrine secretion product of sebaceous glands, plays a central role in the pathogenesis of acne vulgaris. Quantitative (hyperseborrhea) and qualitative changes (dysseborrhea) in acne sebum contribute to Propionibacterium acnes follicular overgrowth, P. acnes biofilm formation, comedogenesis, and inflammation (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar, Zouboulis et al., 2014Zouboulis C.C. Jourdan E. Picardo M. Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions.J Eur Acad Dermatol Venereol. 2014; 28: 527-532Crossref PubMed Scopus (160) Google Scholar). Sebum suppression is, thus, of fundamental importance in treating acne. At present, oral isotretinoin is the most effective sebum-suppressive drug that, via TRAIL-mediated sebocyte apoptosis, decreases the availability of human sebum. However, isotretinoin is associated with the risk of teratogenicity and other apoptosis-related adverse effects, such as depression in a subgroup of predisposed individuals. Systemic anti-androgenic treatment is another sebum-suppressive pharmacological intervention, which, however, is restricted to women taking oral or other forms of contraception. Thus, there is a need to develop effective topical sebum suppressive drugs with fewer adverse effects and applicability for both sexes. Hunt et al., 2017Hunt D.W. Winters G.C. Brownsey R.W. Kulpa J.E. Gilliland K.L. Thiboutot D.M. et al.Inhibition of sebum production with the acetyl coenzyme A carboxylase inhibitor olumacostat glasaretil.J Invest Dermatol. 2017; 137: 1415-1423Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar provide evidence that olumacostat glasaretil (OG), an inhibitor of acetyl coenzyme A carboxylase (ACC), the first committed and rate-limiting step of fatty acid de novo synthesis, reduces saturated and monounsaturated fatty acyl chains in sebaceous lipids. Furthermore, topical OG reduces hamster ear sebaceous gland size. OG (formerly DRM01) is a prodrug that is hydrolyzed by esterases in vivo to form the pharmacologically active compound 5-(tetradecyloxy)-2-furancarboxylic acid, which converts to 5-tetradecyloxy-2-furoyl-coenzyme A (TOFyl-CoA), a fatty acid mimetic that competes with acetyl-CoA, thereby inhibiting the formation of malonyl-CoA (Harwood et al., 2003Harwood Jr., H.J. Petras S.F. Shelly L.D. Zaccaro L.M. Perry D.A. Makowski M.R. et al.Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals.J Biol Chem. 2003; 278: 37099-37111Crossref PubMed Scopus (218) Google Scholar). Malonyl-CoA is the substrate of the multienzyme complex fatty acid synthase, important for acyl chain elongation. This commentary highlights ACC’s key role as a converging point of the major signaling pathways that are important in acne pathogenesis. As discussed, there is good reason to regard saturated and unsaturated sebum fatty acids as crucial players for P. acnes growth, P. acnes biofilm formation, comedogenesis, and NRLP3-driven inflammation (Figure 1). Sebaceous lipid synthesis and desaturase expression depend on the activity of the lipogenic transcription factor SREBP1, which is up-regulated by IGF-1, insulin, and androgens, as well as activation of the nutrient-sensitive kinase mTORC1 (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar). Puberty is physiologically associated with increased serum levels of IGF-1 and androgens. Western diet (consumption of milk and hyperglycemic carbohydrates) further amplifies insulin/IGF-1 signaling (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar). Insulin, IGF-1, androgens, and activated mTORC1, in a synergistic manner, up-regulate the expression of SREBP1, which is the key transcription factor promoting the expression of ACC (Lopez et al., 1996Lopez J.M. Bennett M.K. Sanchez H.B. Rosenfeld J.M. Osborne T.F. Sterol regulation of acetyl coenzyme A carboxylase: a mechanism for coordinate control of cellular lipid.Proc Natl Acad Sci USA. 1996; 93: 1049-1053Crossref PubMed Scopus (248) Google Scholar). In addition, SREBP1 promotes the expression of Δ6-desaturase and stearoyl CoA desaturase (SCD), key enzymes involved in the generation of monounsaturated fatty acids (Nakamura and Nara, 2002Nakamura M.T. Nara T.Y. Gene regulation of mammalian desaturases.Biochem Soc Trans. 2002; 30: 1076-1079Crossref PubMed Scopus (94) Google Scholar). SCD is an iron-containing enzyme that catalyzes a rate-limiting step in the synthesis of unsaturated fatty acids. The principal product of SCD is oleic acid (C18:1Δ9), which is formed by desaturation of stearic acid (C18:0). Thus, SREBP1 not only enhances total sebaceous lipid synthesis but also generates monounsaturated fatty acids such as sapienic acid (C16:1Δ6) and oleic acid, which explains the decreased ratio of saturated/monounsaturated fatty acids of skin surface triacylglycerols in correlation with sebum secretion and acne lesion counts (Smith et al., 2008Smith R.N. Braue A. Varigos G.A. Mann N.J. The effect of a low glycemic load diet on acne vulgaris and the fatty acid composition of skin surface triglycerides.J Dermatol Sci. 2008; 50: 41-52Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). ACC exists as two major isoforms, ACCα and ACCβ, and there is evidence that they play separate roles in the production of malonyl-CoA for fatty acid synthesis and the control of mitochondrial β-oxidation (Munday, 2002Munday M.R. Regulation of mammalian acetyl-CoA carboxylase.Biochem Soc Trans. 2002; 30: 1059-1064Crossref PubMed Scopus (211) Google Scholar). ACC catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, the first committed and rate-limiting step in fatty acid de novo synthesis (Munday, 2002Munday M.R. Regulation of mammalian acetyl-CoA carboxylase.Biochem Soc Trans. 2002; 30: 1059-1064Crossref PubMed Scopus (211) Google Scholar). Thus, ACC plays a central role in the synthesis of saturated fatty acids, which may subsequently be desaturated and incorporated into all major sebaceous lipids that contain acyl chains such as triacylglycerols and wax esters. Malonyl-CoA also increases mitochondrial fatty acid uptake and oxidation, thus providing energy for biosynthetic pathways. Munday and Hemingway, 1999Munday M.R. Hemingway C.J. The regulation of acetyl-CoA carboxylase—a potential target for the action of hypolipidemic agents.Adv Enzyme Regul. 1999; 39: 205-234Crossref PubMed Scopus (84) Google Scholar focused on ACC inhibition as a potential mode of action of hypolipidemic agents and pointed out that fibroyl-CoA esters could inhibit ACC allosterically, just as TOFyl-CoA does. Pharmacological inhibition of ACC has received special attention for the treatment of diabesity and metabolic syndrome (Harwood, 2005Harwood Jr., H.J. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition.Expert Opin Ther Targets. 2005; 9: 267-281Crossref PubMed Scopus (113) Google Scholar), which are all mTORC1-driven diseases of Western civilization (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar). Because fatty acids are essential building blocks for over 85% of human sebum lipids, pharmacological inhibition of ACC is a promising target for sebum suppression and, thus, for acne treatment. Hunt et al., 2017Hunt D.W. Winters G.C. Brownsey R.W. Kulpa J.E. Gilliland K.L. Thiboutot D.M. et al.Inhibition of sebum production with the acetyl coenzyme A carboxylase inhibitor olumacostat glasaretil.J Invest Dermatol. 2017; 137: 1415-1423Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar show that OG inhibits de novo lipid synthesis in primary and transformed human sebocytes and reduces saturated and monounsaturated fatty acyl chains across sebaceous lipids, including triacylglycerols, diacylglycerols, wax esters, cholesteryl esters, and phospholipids. Pioneering studies showed that P. acnes population density correlates significantly with the total amount of sebum lipid produced and the amount of free fatty acids (Gribbon et al., 1993Gribbon E.M. Cunliffe W.J. Holland K.T. Interaction of Propionibacterium acnes with skin lipids in vitro.J Gen Microbiol. 1993; 139: 1745-1751Crossref PubMed Scopus (109) Google Scholar, McGinley et al., 1980McGinley K.J. Webster G.F. Ruggieri M.R. Leyden J.J. Regional variations in density of cutaneous propionibacteria: correlation of Propionibacterium acnes populations with sebaceous secretion.J Clin Microbiol. 1980; 12: 672-675Crossref PubMed Scopus (0) Google Scholar). Oleic acid is one of three critical fatty acids that have been identified as a growth factor of P. acnes influencing its predominant residence (Ushijima et al., 1984Ushijima T. Takahashi M. Ozaki Y. Acetic, propionic, and oleic acid as the possible factors influencing the predominant residence of some species of Propionibacterium and coagulase-negative Staphylococcus on normal human skin.Can J Microbiol. 1984; 30: 647-652Crossref PubMed Scopus (44) Google Scholar). There is recent evidence for the contribution of P. acnes biofilm in acne vulgaris (Jahns et al., 2016Jahns A.C. Eilers H. Alexeyev O.A. Transcriptomic analysis of Propionibacterium acnes biofilms in vitro.Anaerobe. 2016; 42: 111-118Crossref PubMed Scopus (27) Google Scholar). Sessile P. acnes in biofilm excessively secrete the virulence factor triacylglycerol lipase, thus increasing the hydrolysis of fatty acids from sebum triacylglycerols (Coenye et al., 2007Coenye T. Peeters E. Nelis H.J. Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors.Res Microbiol. 2007; 158: 386-392Crossref PubMed Scopus (189) Google Scholar). Free oleic acid, a major component of acne sebum, has been shown to increase P. acnes adherence (Gribbon et al., 1993Gribbon E.M. Cunliffe W.J. Holland K.T. Interaction of Propionibacterium acnes with skin lipids in vitro.J Gen Microbiol. 1993; 139: 1745-1751Crossref PubMed Scopus (109) Google Scholar), which is an initiating step important for P. acnes macrocolony formation. Inhibition of ACC via reducing the concentration of the oleic acid precursor stearic acid may thus compromise oleic acid-mediated P. acnes growth and biofilm formation. Abnormal follicular keratinization is involved in comedogenesis in acne vulgaris. In comedones, more that 90% of triacylglycerols are hydrolyzed to glycerol and free fatty acids (Nicolaides et al., 1970Nicolaides N. Ansari M.N. Fu H.C. Lindsay D.G. Lipid composition on comedones compared with that of human skin surface in acne patients.J Invest Dermatol. 1970; 54: 487-495Abstract Full Text PDF PubMed Scopus (41) Google Scholar). Moreover, acne sebum contains nearly double the amount of diacylglycerols compared with the sebum of acne-free controls. Historical studies by Kligman et al., 1970Kligman A.M. Wheatley V.R. Mills O.H. Comedogenicity of human sebum.Arch Dermatol. 1970; 102: 267-275Crossref PubMed Scopus (86) Google Scholar in the rabbit ear model showed peak comedogenicity for the saturated fatty acids C12:0 and C14:0 and the monounsaturated fatty acids C16:1 and C18:1. Kligman et al., 1970Kligman A.M. Wheatley V.R. Mills O.H. Comedogenicity of human sebum.Arch Dermatol. 1970; 102: 267-275Crossref PubMed Scopus (86) Google Scholar had already emphasized the strong comedogenic effect of oleic acid. Indeed, application of oleic acid and palmitoleic acid (C16:1Δ9) onto hairless mouse skin induced scaly skin, abnormal keratinocyte calcium influx, disturbed keratinization, and epidermal hyperplasia, suggesting that unsaturated fatty acids in sebum alter the calcium dynamics in epidermal keratinocytes and induce abnormal follicular keratinization (Katsuta et al., 2005Katsuta Y. Iida T. Inomata S. Denda M. Unsaturated fatty acids induce calcium influx into keratinocytes and cause abnormal differentiation of epidermis.J Invest Dermatol. 2005; 124: 1008-1013Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). The most convincing fact supporting the causative role of acne sebum in comedogenesis comes from the observation that comedonal acylceramides contain higher amounts palmitic acid (C16:0) and sapienic acid (C16:1Δ6) and much less linoleic acid (C18:2Δ9,Δ12) than do the acylceramides isolated from the skin surface (Perisho et al., 1988Perisho K. Wertz P.W. Madison K.C. Stewart M.E. Downing D.T. Fatty acids of acylceramides from comedones and from the skin surface of acne patients and control subjects.J Invest Dermatol. 1988; 90: 350-353Abstract Full Text PDF PubMed Scopus (46) Google Scholar). Because sapienic acid cannot be synthesized by keratinocytes and is, thus, a unique sebocyte-specific fatty acid, it can only be of sebaceous origin. Sebum-derived sapienic and palmitic acid are taken up by infundibular keratinocytes and are incorporated into keratinocyte-specific acylceramides (Perisho et al., 1988Perisho K. Wertz P.W. Madison K.C. Stewart M.E. Downing D.T. Fatty acids of acylceramides from comedones and from the skin surface of acne patients and control subjects.J Invest Dermatol. 1988; 90: 350-353Abstract Full Text PDF PubMed Scopus (46) Google Scholar). It has been suggested that the replacement of linoleate in acylceramides of infundibular keratinocytes disturbs infundibular barrier function and induces comedogenesis (Perisho et al., 1988Perisho K. Wertz P.W. Madison K.C. Stewart M.E. Downing D.T. Fatty acids of acylceramides from comedones and from the skin surface of acne patients and control subjects.J Invest Dermatol. 1988; 90: 350-353Abstract Full Text PDF PubMed Scopus (46) Google Scholar). In fact, application of human sebum to hairless mouse skin disrupts epidermal barrier function, resulting in enhanced production of proinflammatory cytokines including IL-1α (Guo et al., 2015Guo J.W. Lin T.K. Wu C.H. Wei K.C. Lan C.C. Peng A.C. et al.Human sebum extract induces barrier disruption and cytokine expression in murine epidermis.J Dermatol Sci. 2015; 78: 34-43Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar), which had already been linked to comedogenesis (Ingham et al., 1992Ingham E. Eady E.A. Goodwin C.E. Cove J.H. Cunliffe W.J. Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris.J Invest Dermatol. 1992; 98: 895-901Abstract Full Text PDF PubMed Scopus (156) Google Scholar). Selway et al., 2013Selway J.L. Kurczab T. Kealey T. Langlands K. Toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne.BMC Dermatol. 2013; 13: 10Crossref PubMed Scopus (63) Google Scholar reported that toll-like receptor (TLR) 2 is expressed in basal and infundibular keratinocytes and in sebaceous glands and that its activation provoked the release of IL-1α from primary human keratinocytes in vitro. Furthermore, exposure of microdissected human sebaceous glands to pathogen-associated molecular patterns specific for TLR2 in vitro resulted in a pattern of IL-1α–like cornification after 7 days of exposure (Selway et al., 2013Selway J.L. Kurczab T. Kealey T. Langlands K. Toll-like receptor 2 activation and comedogenesis: implications for the pathogenesis of acne.BMC Dermatol. 2013; 13: 10Crossref PubMed Scopus (63) Google Scholar). Free palmitic acid, oleic acid, and diacylglycerols have been identified as danger signals (pathogen-associated molecular patterns) that bind to TLR2 and thereby activate the NLRP3 inflammasome (Huang et al., 2012Huang S. Rutkowsky J.M. Snodgrass R.G. Ono-Moore K.D. Schneider D.A. Newman J.W. et al.Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways.J Lipid Res. 2012; 53: 2002-2013Crossref PubMed Scopus (422) Google Scholar, Tse et al., 2015Tse E. Helbig K.J. Van der Hoek K. McCartney E.M. Van der Hoek M. George J. et al.Fatty acids induce a pro-Inflammatory gene expression profile in Huh-7 cells that attenuates the anti-HCV action of interferon.J Interferon Cytokine Res. 2015; 35: 392-400Crossref PubMed Scopus (12) Google Scholar). P. acnes, whose growth and biofilm formation depend on the availability of oleic acid, also interacts with TLR2 (Su et al., 2016Su Q. Grabowski M. Weindl G. Recognition of Propionibacterium acnes by human TLR2 heterodimers.Int J Med Microbiol. 2016; ([e-pub ahead of print])https://doi.org/10.1016/j.ijmm.2016.12.002Crossref PubMed Scopus (29) Google Scholar). It has been shown that P. acnes, via TLR2 signaling, activates the NLRP3 inflammasome in human sebocytes (Li et al., 2014Li Z.J. Choi D.K. Sohn K.C. Seo M.S. Lee H.E. Lee Y. et al.Propionibacterium acnes activates the NLRP3 inflammasome in human sebocytes.J Invest Dermatol. 2014; 134: 2747-2756Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Subsequent release of IL-1β orchestrates the T helper type 17 lymphocyte response found in acne lesions (Kelhälä et al., 2014Kelhälä H.L. Palatsi R. Fyhrquist N. Lehtimäki S. Väyrynen J.P. Kallioinen M. et al.IL17/Th17 pathway is activated in acne lesions.PLoS One. 2014; 9: e105238Crossref PubMed Scopus (103) Google Scholar). Thus, sebum-derived free fatty acids, especially palmitic and oleic acid, released by the enzymatic activity of P. acnes triacylglycerol lipase, promote TLR2 signaling. Oleic acid-mediated promotion of P. acnes growth and macrocolony formation further enhances P. acnes-stimulated TLR2 activation. In a feed-forward loop, TLR2 activation promotes the expression of SCD1 in human sebocytes, the key enzyme that desaturates stearic acid to oleic acid. Thus, there is accumulating evidence for the role of sebum-free fatty acids as direct and indirect key drivers orchestrating the sebofollicular inflammasomopathy in acne vulgaris (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar) (Figure 1). The inhibition of ACC, the rate-limiting enzyme of fatty acid de novo synthesis, is an attractive target for sebum suppression. Because the action of ACC and the biosynthesis of saturated fatty acids operate upstream of the action of desaturases, which require saturated acyl chains as substrates (Figure 1), ACC inhibition should reduce total amounts of sebaceous lipids, including saturated and monounsaturated fatty acids. In fact, Hunt et al., 2017Hunt D.W. Winters G.C. Brownsey R.W. Kulpa J.E. Gilliland K.L. Thiboutot D.M. et al.Inhibition of sebum production with the acetyl coenzyme A carboxylase inhibitor olumacostat glasaretil.J Invest Dermatol. 2017; 137: 1415-1423Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar have shown inhibition of de novo lipid synthesis and reduction of saturated and monounsaturated fatty acyl chains in all major lipid classes of OG-treated sebocytes. Noteworthy is the clinical observation that a direct correlation exists between sebum reduction and acne improvement (Janiczek-Dolphin et al., 2010Janiczek-Dolphin N. Cook J. Thiboutot D. Harness J. Clucas A. Can sebum reduction predict acne outcome?.Br J Dermatol. 2010; 163: 683-688Crossref PubMed Scopus (52) Google Scholar). In accordance, a recent phase IIa, multicenter, randomized, vehicle-controlled study with 7.5% OG gel has presented evidence of therapeutic efficacy in patients with moderate to severe facial acne vulgaris (Bissonnette et al., 2017Bissonnette R. Poulin Y. Drew J. Hofland H. Tan J. Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: a phase IIa, multicenter, randomized, vehicle-controlled study.J Am Acad Dermatol. 2017; 76: 33-39Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). At week 12, OG treatment showed greater reductions from baseline in inflammatory lesions and noninflammatory lesions and more patients with a two-grade or greater improvement in investigator global assessment scores than vehicle (Bissonnette et al., 2017Bissonnette R. Poulin Y. Drew J. Hofland H. Tan J. Olumacostat glasaretil, a novel topical sebum inhibitor, in the treatment of acne vulgaris: a phase IIa, multicenter, randomized, vehicle-controlled study.J Am Acad Dermatol. 2017; 76: 33-39Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Acne vulgaris, a disease of Western civilization, can be regarded as the metabolic syndrome of the skin (Melnik, 2015Melnik B.C. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.Clin Cosmet Investig Dermatol. 2015; 8: 371-388Crossref PubMed Scopus (128) Google Scholar). A decade ago, ACC inhibition had already been proposed to exert favorable effects in treating the metabolic syndrome (Harwood, 2005Harwood Jr., H.J. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition.Expert Opin Ther Targets. 2005; 9: 267-281Crossref PubMed Scopus (113) Google Scholar). Topical OG-mediated ACC inhibition in concert with sebum-suppressive dietary interventions, which synergistically attenuate SREBP1-mediated ACC expression, may be promising options for treating acne vulgaris, exhibiting fewer adverse effects compared with systemic isotretinoin treatment. The author states no conflict of interest.