Cholesterolgenic Inhibition Causes Permanent Hair Follicle Damage by Activating Fibrosis Via the Angiotensin Receptor


  • Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala
  • Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala
  • Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala
  • Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala
  • Department of Zoology, Advanced Centre for Regenerative Medicine and Stem cell in Cutaneous Research (AcREM-Stem), University of Kerala, Thiruvananthapuram – 695581, Kerala



Aryl hydrocarbon Receptor, Angiotensin II, Primary Cicatricial Alopecia, Autoimmune Disorder, Peroxisome Proliferator-Activated Receptors γ, Transforming Growth Factor β


Primary Cicatricial Alopecia (PCA) is a type of inflammatory hair loss disorder that resulted in the permanent damage of the pilosebaceous structure due to fibrosis. Various internal and environmental stimuli caused the breakdown of hair follicle cells. Cholesterol is a crucial component in the formation and differentiation of hair follicles and the overall health of the skin. The loss of hair follicle and aberrant cycles were caused by any inhibition or obstruction of the cholesterol biosynthetic pathways. This study suggests that cholesterologenic changes like precursor formation and inhibition in the hair follicle, trigger inflammation, fibrogenic signaling and leading to fibrosis. TGFβ-SMAD pathways related to the fibrogenic process were significantly expressed during the experimental condition. Angiotensin II receptor, AGTR1, showed a profound effect on the hair follicle cells. Real-time PCR analysis and immunohistochemistry of the patient’s scalp biopsies, HHFORS cells, and mice tissue sample revealed that the fibrotic genes were significantly activated after the treatment of BM15766, a cholesterol biosynthesis inhibitor, and 7- DHC, a sterol precursor. Our study confirmed that fibrosis is developed in the late stage of PCA by the dysregulation of cholesterol biosynthesis pathways in the hair follicle cells.


Download data is not yet available.


Metrics Loading ...


Inoue T, Miki Y, Abe K, et al. Sex steroid synthesis in human skin in situ : The roles of aromatase and steroidogenic acute regulatory protein in the homeostasis of human skin. Mol Cell Endocrinol. 2012; 362(1-2):19-28. PMid:22634420

Tsuruoka H, Khovidhunkit W, Brown BE, et al. Scavenger Receptor Class B Type I is Expressed in Cultured Keratinocytes and Epidermis regulation in response to changes in cholesterol homeostasis and barrier. 2002; 277(4):2916-22. PMid:11707442

Schallreuter KU, Hasse S, Rokos H, et al. Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells. Exp Dermatol. 2009; 18(8):680-8. PMid:19469904

Palmer M, Palmer MA, Blakeborough L, et al. Cholesterol homeostasis : Links to hair follicle biology and hair disorders.Exp Dermatol. 2020; 29(3):299-311. PMid:31260136

Panicker SP, Ganguly T, Consolo M, et al. Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia. PLoS One. 2012; 7(6):e38449:. PMid:22685570 PMCid:PMC3369908

Ozyurt K, Uzak A, Ozturk P, et al. Emopamil binding protein mutation in Conradi-Hünermann-Happle syndrome representing plaque-type psoriasis. Indian J Dermatol. 2015; 60(2):216.

Frangogiannis NG. Transforming growth factor-ß in tissue fibrosis. J Exp Med. 2020; 217(3):1-16. jem.20190103 PMid:32997468 PMCid:PMC7062524

8. Wei J, Ghosh AK, Sargent JL, et al. PPARγ downregulation by TGF in fibroblast and impaired expression and function in systemic sclerosis: A novel mechanism for progressive fibrogenesis. PLoS One. 2010; 5(11):e13778. journal.pone.0013778 PMid:21072170 PMCid:PMC2970611

Inagaki Y, Okazaki I. Emerging insights into transforming growth factor β Smad signal in hepatic fibrogenesis. Gut. 2007; 56(2):284-92. PMid:17303605 PMCid:PMC1856752

Kagami S, Border WA, Miller DE, Noble NA. Angiotensin 11 Stimulates extracellular matrix protein synthesis through induction of transforming growth factor- β expression in rat glomerular mesangial cells. J Clin Invest. 1994; 93(6):2431-7. https://doi. org/10.1172/JCI117251 PMid:8200978 PMCid:PMC294451

Suresh S, Leemon N, Najeeb S, Panicker SP. Cytokine profiling in primary cicatricial alopecia : androgenic alopecia and leptin connections. Journal of Endocrinology and Reproduction. 2020; 24:87-96.

Shapira KE, Ehrlich M, Henis YI. Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism. Mol Biol Cell. 2018; 29(20):2494-507. PMid:30091670 PMCid:PMC6233055

Ito T, Ito N, Saathoff M, et al. Interferon-γ is a potent inducer of catagen-like changes in cultured human anagen hair follicles. Br J Dermatol. 2005; 152(4):623-31. PMid:15840090

Imanishi H, Ansell DM, Chéret J, et al. Epithelial-to-mesenchymal stem cell transition in a human organ: lessons from lichen planopilaris. J Invest Dermatol. 2018; 138(3):511-9. PMid:29106928

Budi EH, Duan D, Derynck R. Transforming Growth Factor- b Receptors and Smads :Regulatory complexity and functional versatility. Trends Cell Biol. 2017; 27(9):658-672. PMid:28552280

Roberts AB, Sporn MB. Mini-Review: Physiological actions and clinical applications of transforming growth factor beta ( TGFBeta ). Growth Factors. 1993; 8:1-9. PMid:8448037

Lu L, Saulis AS, Liu WR, et al. The temporal effects of anti-TGF-β1, 2, and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg. 2005; 201(3):391-7. PMid:16125072

Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical role of transforming growth factor beta in different phases of wound healing. Adv Wound Care. 2013; 2(5):215-24. PMid:24527344 PMCid:PMC3857353

Hitraya EG, Varga J, Artlett CM, Jimenjz SA. Identification of elements in the promoter region of the alpha1(1) procollagen gene involved in its up-regulated expression in systemic sclerosis. Arthritis Rheum. 1998; 41(11):2048-58. 0131(199811)41:11<2048::AID-ART21>3.0.CO;2-X

Tang H, Cheng D, Jia Y, et al. Angiotensin II induces type I collagen gene expression in human dermal fibroblasts through an AP-1 / TGF- b 1-dependent pathway. Biochem Biophys Res Commun. 2009; 385(3):418-23. PMid:19465003

Namazi MR, Ashraf A, Handjani F, et al. Angiotensin converting enzyme activity in alopecia areata. Enzyme Res. 2014; 2014:694148. PMid:25349723 PMCid:PMC4198813

Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis.Fibrogenesis Tissue Repair. 2015; 23;8:7. PMid:25949522 PMCid:PMC4422447

Gabriel VA. Transforming growth factor- β and angiotensin in fibrosis and burn injuries. J Burn Care Res. 2009; 30(3):471-481. PMid:19349880

Zuo W, Zhao X, Chen YG. SARS Coronavirus and Lung Fibrosis. Molecular Biology of the SARS-Coronavirus. 2009; 22:247-58. PMCid:PMC7176214

Karnik P, Tekeste Z, McCormick TS, et al. Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J Invest Dermatol 2009; 129(5):1243-57. PMid:19052558 PMCid:PMC3130601

Shi-wen X, Eastwood M, Stratton RJ, et al. Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts. Rheumatology 2010; 49(2):259-63. PMid:20007285

Vallée A, Lecarpentier Y. TGF β in fibrosis by acting as a conductor for contractile properties of myofibroblasts. Cell Biosci. 2019; 1-15. PMid:31827764 PMCid:PMC6902440

Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett. 2007; 581(19):3608-15. PMid:17412325

He J, Hu B, Shi X, et al. Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase sirt3. Mol Cell Biol. 2013; 33(10):2047-55. PMid:23508103 PMCid:PMC3647969

Kolf-Clauw M, Chevy F, Siliart B, et al. Cholesterol biosynthesis inhibited by BM15.766 induces holoprosencephaly in the rat. Teratology. 1997; 56(3):188-200.<188::AID-TERA2>3.0.CO;2-Y

Müller-Röver S, Handjiski B, Van Der Veen C, et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 2001 ;117(1):3-15. PMid:11442744

Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev. 2001; 81(1):449-94. PMid:11152763

Hanlon PR, Ganem LG, Cho YC, et al. AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ1 expression and subsequent adipocyte differentiation. Toxicol Appl Pharmacol. 2003; 189(1):11-27.

Cimafranca MA, Hanlon PR, Jefcoate CR. TCDD administration after the pro-adipogenic differentiation stimulus inhibits PPARγ through a MEK-dependent process but less effectively suppresses adipogenesis. Toxicol Appl Pharmacol. 2004; 196(1):156-68. PMid:15050417

Ayers NB, Sun C, Chen SY. Transforming growth factor-β signaling in systemic sclerosis. J Biomed Res. 2018; 32(1):3-12. 36. Shimizu A, Kato M, Nakao A, et al. Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line. Genes Cells. 1998; 3(2):125-134. PMid:9605406

Wang W, Huang XR, Canlas E, et al. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res. 2006; 98(8):1032- 9. PMid:16556868 PMCid:PMC1450325

Shi Y, Massague J. Mechanisms of TGF- β Signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. https://doi. org/10.1016/S0092-8674(03)00432-X

Pierreux CE, Nicolás FJ, Hill CS. Transforming growth factor β-independent shuttling of smad4 between the cytoplasm and nucleus. Mol Cell Biol. 2000; 20(23):9041-54. PMid:11074002 PMCid:PMC86557

Puolakkainen PA, Reed MJ, Gombotz WR, Twardzik DR, Abrass IB, Helene Sage E. Acceleration of wound healing in aged rats by topical application of transforming growth factor‐β1. Wound Repair Regen. 1995; 3(3):330-9. 475X.1995.t01-1-30314.x PMid:17173560

Leask A, Abraham DJ. TGF‐β signaling and the fibrotic response. FASEB J. 2004; 18(7):816-27. 1273rev PMid:15117886

Isaka Y. Targeting TGF-β signaling in kidney fibrosis. Int J Mol Sci. 2018; 19(9):1-13. PMid:30150520 PMCid:PMC6165001

Kulozik M, Hogg A, Lankat-Buttgereit B, Krieg T. Co-localization of transforming growth factor β2 with α1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest. 1990; 86(3):917-22. PMid:1697606 PMCid:PMC296811

Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol Med. 2011; 17(1-2):113-25. PMid:20927486 PMCid:PMC3022978

Martinez-ferrer M, Afzar-Sheriff A-R, Uwamariya C, et al. Dermal transforming growth factor- β responsiveness mediates wound contraction and epithelial closure. Am J Pathol. 2010; 176(1):98-107. PMid:19959810 PMCid:PMC2797873

46. Nagy P, Schaff Z, Lapis K. Immunohistochemical detection of transforming growth factor β, in Fibrotic liver diseases. Hepatology. 1991; 14(2):269-73. PMid:1713566

Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 2007; 56(1):334-44. https://doi. org/10.1002/art.22328 PMid:17195237

Pierre S, Chevallier A, Teixeira-Clerc F, et al. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol Sci. 2014; 137(1):114-24. PMid:24154488

Marut W, Kavian N, Hua-huy T, et al. Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade. Arthritis Rheum. 2013; 65(5):1367-77. PMid:23335130

Steckelings UM, Wollschlager T, Peters J, et al. Human skin: Source of and target organ for angiotensin II. Exp Dermatol. 2004; 13(3):148-54. PMid:14987254

Wei J. Regulation of matrix remodeling by peroxisome proliferator-activated receptor-γ: A novel link between metabolism and fibrogenesis. Open Rheumatol J. 2012; 6(1):103-15. PMid:22802908 PMCid:PMC3396343

Culver DA, Barna BP, Raychaudhuri B, et al. Peroxisome proliferator-activated receptor γ activity is deficient in alveolar macrophages in pulmonary sarcoidosis. Am J Respir Cell Mol Biol. 2004; 30(1):1-5. PMid:14512375

Miyahara T, Schrum L, Rippe R, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000; 275(46):35715-22. PMid:10969082

Zheng F, Fornoni A, Elliot SJ, et al. Upregulation of type I collagen by TGF-β in mesangial cells is blocked by PPARγ activation. Am J Physiol - Ren Physiol. 2002; 282(4):F639-48. PMid:11880325

Burgess HA, Daugherty LE, Thatcher TH, et al. PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and collagen production: Implications for therapy of lung fibrosis. Am J Physiol - Lung Cell Mol Physiol. 2005; 288(6):L1146-53. PMid:15734787

Ghosh AK, Wei J, Wu M, Varga J. Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-γ. Biochem Biophys Res Commun. 2008; 374(2):231-6. https://doi. org/10.1016/j.bbrc.2008.07.014 PMid:18627765 PMCid:PMC3157939

Matabosch X, Ying L, Watson G, Shackleton C. Hair and skin sterols in normal mice and those with deficient dehydrosterol reductase ( DHCR7 ), the enzyme associated with Smith-Lemli-Opitz syndrome. J Steroid Biochem Mol Biol. 2010; 122(5):318- 25. PMid:20804844 PMCid:PMC2964438




How to Cite

Najeeb, S. H., Binumon, T. M., Surya, S., Nikhila, L., & Sreejith, P. P. (2022). Cholesterolgenic Inhibition Causes Permanent Hair Follicle Damage by Activating Fibrosis Via the Angiotensin Receptor. Journal of Endocrinology and Reproduction, 26(3), 187–204.



Original Research