Open Access Open Access  Restricted Access Subscription or Fee Access

A Plan for Nutraceutical/Dietary Management of Acne Targeting De Novo Lipogenesis and Inflammation

Aaron Lerner, Carina Benzvi, Mark F. McCarty


The pathogenesis of acne involves an excess of sebum production. Sebum is a fatty substance produced by de novo lipogenesis (DNL) in sebocytes. A key driver of DNL is the transcription factor steroid response element-binding protein 1-c (SREBP-1c), promoted by insulin-like growth factor-1 (IGF-1)-mediated activation of Akt. Akt disinhibits the LXR-mediated transcription of the SREBP-1c
gene by promoting nuclear exclusion of FOXO1; concurrently, it promotes proteolytic activation SREBP-1c, while enhancing its half-life, via mTORC1-p70 S6 kinase signaling. Adenosine 5′- monophosphate-activated protein kinase (AMPK) can oppose SREBP-1c activity by suppressing LXR expression, while also inhibiting mTORC1; in addition, it also opposes DNL via direct inhibition of acetyl-coA carboxylase 1 (ACC1). Sirtuin 1 (Sirt1) inhibits the transactivational activity of SREBP-1c by deacetylating it, and also boosts AMPK activity. It is proposed that nutraceuticals which activate AMPK (such as berberine) and Sirt1 (such as ferulic acid, methylnicotinamide, and melatonin) thus inhibiting sebocyte DNL. Bacterially driven inflammation may be suppressed with nutraceutical antioxidants such as spirulina, lipoic acid, N-acetylcysteine, and supplemental fish oil. Dietary wise, the plasma free IGF-1 which promotes sebocyte DNL could be reduced with low-protein plant-based diets or low-glycemic-load “Paleolithic” diets – consistent with the observation that acne is a
“disease of civilization”. Practical Applications: The present review is focused on feasible nutraceutical strategies for Acne therapy targeting de novo Lipogenesis and Inflammation. The topic of nutraceuticals that down-regulate those two major pathological pathways in Acne development is a new evolving therapeutical strategy. The mechanisms are reported, and the different nutraceuticals interact in a complementary fashion to reduce risk of Acne, while also helping to prevent it. Additionally, the present review reports practical daily dose ranges for those nutraceuticals that might be expected to have physiological activity. To our knowledge, such an updated manuscript, on
the topic of Acne and nutraceuticals is not available in the food or medical literature.

Full Text:



Meixiong J, Ricco C, Vasavda C, Ho BK. Diet and acne: A systematic review. JAAD Int 2022; 7: 95-112.

Chen H, Zhang TC, Yin XL, et al. Magnitude and temporal trend of acne vulgaris burden in 204 countries and territories from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019. Br J Dermatol 2022; 186: 673-83.

Bataille V, Snieder H, MacGregor AJ, et al. The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women. J Invest Dermatol 2002; 119(6): 1317-22.

Yang J, Yang H, Xu A, He L. A Review of Advancement on Influencing Factors of Acne: An Emphasis on Environment Characteristics. Front Public Health 2020; 8: 450.

Lerner A, Aminov R, Matthias T. Dysbiosis May Trigger Autoimmune Diseases via Inappropriate Post-Translational Modification of Host Proteins. Front Microbiol 2016; 7: 84.

Wilkins LJ, Monga M, Miller AW. Defining Dysbiosis for a Cluster of Chronic Diseases. Sci Rep 2019; 9: 12918.

Dreno B, Dagnelie MA, Khammari A, Corvec S. The Skin Microbiome: A New Actor in Inflammatory Acne. Am J Clin Dermatol 2020; 21(Suppl 1): 18-24.

Branisteanu DE, Toader MP, Porumb EA, et al. Adult female acne: Clinical and therapeutic particularities (Review). Exp Ther Med 2022; 23: 151.

Carmina E, Dreno B, Lucky WA, et al. Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee. J Endocr Soc 2022; 6:


Nahum R, Thong KJ, Hillier SG. Metabolic regulation of androgen production by human thecal cells in vitro. Hum Reprod 1995; 10: 75-81.

Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997; 15: 111-22.

Barrault C, Garnier J, Pedretti N, et al. Androgens induce sebaceous differentiation in sebocyte cells expressing a stable functional androgen receptor. J Steroid Biochem Mol Biol 2015; 152: 34-44.

Melnik BC. Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity. Acta Derm Venereol 2017; 97: 173-81.

Moon YA. The SCAP/SREBP Pathway: A Mediator of Hepatic Steatosis. Endocrinol Metab (Seoul ) 2017; 32: 6-10.

Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol 2008; 128: 1286-93.

Yoshikawa T, Shimano H, Amemiya-Kudo M, et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 2001; 21: 2991-3000.

Yang J, Craddock L, Hong S, Liu ZM. AMP-activated protein kinase suppresses LXR-dependent sterol regulatory element-binding protein-1c transcription in rat hepatoma McA-RH7777 cells. J Cell Biochem 2009; 106: 414-26.

Owen JL, Zhang Y, Bae SH, et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci U S A 2012; 109: 16184-9.

Dong Q, Majumdar G, O'Meally RN, et al. Insulin-induced de novo lipid synthesis occurs mainly

via mTOR-dependent regulation of proteostasis of SREBP-1c. Mol Cell Biochem 2020; 463: 13-31.

Velasco G, Geelen MJ, Guzman M. Control of hepatic fatty acid oxidation by 5'-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism.

Arch Biochem Biophys 1997; 337: 169-75.

Zhou G, Sebhat IK, Zhang BB. AMPK activators--potential therapeutics for metabolic and other diseases. Acta Physiol (Oxf) 2009; 196: 175-90.

Xie L, Zhang D, Ma H, et al. The Effect of Berberine on Reproduction and Metabolism in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Control Trials. Evid Based Complement Alternat Med 2019;2019: 7918631.

Mishra N, Verma R, Jadaun P. Study on the Effect of Berberine, Myoinositol, and Metformin in Women with Polycystic Ovary Syndrome: A Prospective Randomised Study. Cureus 2022; 14: e21781.

Rondanelli M, Riva A, Petrangolini G, et al. Berberine Phospholipid Is an Effective Insulin Sensitizer and Improves Metabolic and Hormonal Disorders in Women with Polycystic Ovary Syndrome: A One-Group Pretest-Post-Test Explanatory Study. Nutrients 2021; 13.

Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 2008; 283: 27628-35.

Hou X, Xu S, Maitland-Toolan KA, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008; 283: 20015-26.

Ponugoti B, Kim DH, Xiao Z, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010; 285: 33959-70.

Wei Z, Chen G, Hu T, et al. Resveratrol ameliorates lipid accumulation and inflammation in human SZ95 sebocytes via the AMPK signaling pathways in vitro. J Dermatol Sci 2021; 103:


Chimento A, De Amicis F, Sirianni R, et al. Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol. Int J Mol Sci 2019; 20.

El-Mesallamy HO, Gawish RA, Sallam AM, et al. Ferulic acid protects against radiation-induced testicular damage in male rats: impact on SIRT1 and PARP1. Environ Sci Pollut Res Int 2018; 25: 6218-27.

Moghadam FH, Mesbah-Ardakani M, Nasr-Esfahani MH. Ferulic Acid exerts concentration- dependent anti-apoptotic and neuronal differentiation-inducing effects in PC12 and mouse neural

stem cells. Eur J Pharmacol 2018; 841: 104-12.

Hou T, Zhang L, Yang X. Ferulic acid, a natural polyphenol, protects against osteoporosis by activating SIRT1 and NF-κB in neonatal rats with glucocorticoid-induced osteoporosis. Biomed Pharmacother 2019; 120: 109205.

Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012; 15: 838-47.

Leduc-Gaudet JP, Dulac M, Reynaud O, et al. Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole-body glucose homeostasis: does it actually work in humans? J Physiol 2020; 598: 619-20.

Leduc-Gaudet JP, Dulac M, Reynaud O, et al. Nicotinamide riboside supplementation to improve skeletal muscle mitochondrial health and whole-body glucose homeostasis: does it actually work in humans? J Physiol 2020; 598: 619-20.

Hong S, Moreno-Navarrete JM, et al. Nicotinamide N methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nat Med 2015; 21: 887-94.

Takeuchi K, Yokouchi C, Goto H, et al. Alleviation of fatty liver in a rat model by enhancing N(1)-methylnicotinamide bioavailability through aldehyde oxidase inhibition. Biochem Biophys Res Commun 2018; 507: 203-10.

Zhang J, Chen Y, Liu C, Li L, Li P. N(1)-Methylnicotinamide Improves Hepatic Insulin Sensitivity via Activation of SIRT1 and Inhibition of FOXO1 Acetylation. J Diabetes Res 2020; 2020: 1080152.

Cristòfol R, Porquet D, Corpas R, et al. Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. J Pineal Res 2012; 52: 271-81.

Yu L, Sun Y, Cheng L, et al.Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1. J Pineal Res 2014; 57: 228-38.

Yang Y, Jiang S, Dong Y, et al. Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 2015; 58: 61-70.

Yang Y, Bai T, Yao YL, et al. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol Lett 2016; 262: 80-91.

Velagapudi R, El-Bakoush A, Lepiarz I, et al. AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Mol Cell Biochem 2017; 435: 149-62.

Karandrea S, Yin H, Liang X, Slitt AL, Heart EA. Thymoquinone ameliorates diabetic phenotype in Diet-Induced Obesity mice via activation of SIRT-1-dependent pathways. PLoS One 2017; 12:


Lu Y, Feng Y, Liu D, et al. Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling. Cell Physiol Biochem 2018; 47: 1193-206.

Salam SA, Mostafa F, Alnamshan MM, et al. Thymoquinone ameliorates age-related hearing loss in C57BL/6J mice by modulating Sirt1 activity and Bak1 expression. Biomed Pharmacother

; 143: 112149.

Li K, Zhai M, Jiang L, et al. Tetrahydrocurcumin Ameliorates Diabetic Cardiomyopathy by Attenuating High Glucose-Induced Oxidative Stress and Fibrosis via Activating the SIRT1 Pathway. Oxid Med Cell Longev 2019; 2019: 6746907.

Li L, Liu X, Li S, et al. Tetrahydrocurcumin protects against sepsis-induced acute kidney injury via the SIRT1 pathway. Ren Fail 2021; 43: 1028-40.

McCarty MF. Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy. Int J Mol Sci 2022; 23.

Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 2004; 23: 2369-80.

Saitoh M, Nishitoh H, Fujii M, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 1998; 17: 2596-606.

Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D. The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid. J Physiol Pharmacol 2013; 64: 409-21.

Li Q, Spencer NY, Oakley FD, et al. Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha. Antioxid Redox Signal 2009; 11: 1249-63.

McCarty MF. Clinical potential of Spirulina as a source of phycocyanobilin. J Med Food 2007; 10: 566-70.

Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008; 74: 1526-39.

Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7: 355-9.

Montes LF, Wilborn WH, Montes CM. Topical acne treatment with acetylcysteine: clinical and experimental effects. Skinmed 2012; 10: 348-51.

Mardani N, Mozafarpoor S, Goodarzi A, Nikkhah F. A systematic review of N-acetylcysteine for treatment of acne vulgaris and acne-related associations and consequences: Focus on clinical studies. Dermatol Ther 2021; 34: e14915.

Aslan Ä, Özcan F, Karaarslan T, et al. Decreased eicosapentaenoic acid levels in acne vulgaris reveals the presence of a proinflammatory state. Prostaglandins Other Lipid Mediat 2017; 128- 129: 1-7.

Jung JY, Kwon HH, Hong JS, et al. Effect of dietary supplementation with omega-3 fatty acid and gamma-linolenic acid on acne vulgaris: a randomised, double-blind, controlled trial. Acta Derm Venereol 2014; 94: 521-5.

Smith TM, Cong Z, Gilliland KL, et al. Insulin-like growth factor-1 induces lipid production in human SEB-1 sebocytes via sterol response element-binding protein-1. J Invest Dermatol 2006; 126: 1226-32.

Smith TM, Gilliland K, Clawson GA, Thiboutot D. IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol 2008; 128: 1286-93.

Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009; 18: 833-41.

Liu X, Qiao A, Ke Y, et al. FoxO1 represses LXRα-mediated transcriptional activity of SREBP- 1c promoter in HepG2 cells. FEBS Lett 2010; 584: 4330-4.

Deng X, Zhang W, Sullivan I, et al. FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 2012; 287: 20132-43.

Cappel M, Mauger D, Thiboutot D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women. Arch Dermatol 2005; 141: 333-8.

Rahaman SMA, De D, Handa S, et al. Association of insulin-like growth factor (IGF)-1 gene polymorphisms with plasma levels of IGF-1 and acne severity. J Am Acad Dermatol 2016; 75: 768-73.

Fontana L, Weiss EP, Villareal DT, et al. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 2008; 7: 681-7.

McCarty MF. GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. Med Hypotheses 2014; 83: 365-71.

Castano-Martinez T, Schumacher F, Schumacher S, et al. Methionine restriction prevents onset of type 2 diabetes in NZO mice. FASEB J 2019; 33: 7092-102.

Banaszak M, Gorna I, Przyslawski J. Non-Pharmacological Treatments for Insulin Resistance: Effective Intervention of Plant-Based Diets-A Critical Review. Nutrients 2022; 14.

Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009; 18: 833-41.

Smith RN, Mann NJ, Braue A, et al. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial. J Am Acad Dermatol 2007; 57: 247-56.

Smith RN, Mann NJ, Braue A, et al. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007; 86: 107-15.

Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Western civilization. Arch Dermatol 2002; 138: 1584-90.

Clatici VG, Voicu C, Voaides C, et al. Diseases of Civilization - Cancer, Diabetes, Obesity and Acne - the Implication of Milk, IGF-1 and mTORC1. Maedica (Bucur ) 2018; 13: 273-81.

Juhl CR, Bergholdt HKM, Miller IM, et al. Dairy Intake and Acne Vulgaris: A Systematic Review and Meta-Analysis of 78,529 Children, Adolescents, and Young Adults. Nutrients 2018;

Stevenson EJ, Allerton DM. The role of whey protein in postprandial glycaemic control. Proc Nutr Soc 2018; 77: 42-51.


  • There are currently no refbacks.