Linoleic acid improves rosacea through repairing mitochondrial damage in keratinocytes

Abstract

Rosacea, as a progressive and chronic inflammatory skin disease, lacks safe and effective treatment options. Our previous study reported metabolic disturbance in rosacea patients, containing abnormal lipid metabolism. Building on this, we characterized significant alterations in fatty acid metabolism among rosacea patients, with a notable increase in linoleic acid (LNA) levels. We further demonstrated that LNA prevents rosacea-like dermatitis in LL37-induced rosacea-like mouse model. Our evidence indicated that LNA hyperactivates PPARγ signaling in the epidermis, a phenomenon observed in both rosacea patients and mouse model. Inhibiting PPARγ rescued the effect of LNA in LL37-induced mice. Additionally, our in vivo and in vitro evidence strongly supported the presence of mitochondrial damage in the keratinocytes of rosacea. LNA stimulated PPARγ to reduce the reactive oxygen species production, increasing the generation of ATP and recovering mitochondrial membrane potential. Finally, through a prospective cohort study utilizing UK Biobank data and linkage disequilibrium score regression (LDSC) regression analysis, we further confirmed LNA levels are negatively related to the risk of rosacea, highlighting LNA as a promising therapeutic strategy for rosacea treatment.

Keywords

rosacea / linoleic acid / PPARγ / mitochondrial damage

References

[1] Thiboutot D , Anderson R , Cook-Bolden F , et al. Standard management options for rosacea: the 2019 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol 2020; 82: 1501- 10.

[2] Gether L , Overgaard LK , Egeberg A , et al. Incidence and prevalence of rosacea: a systematic review and meta-analysis. Br J Dermatol 2018; 179: 282- 9.

[3] Li J , Wang B , Deng Y , et al. Epidemiological features of rosacea in Changsha, China: a population-based, cross-sectional study. J Dermatol 2020; 47: 497- 502.

[4] Woo YR , Lim JH , Cho DH , et al. Rosacea: molecular mechanisms and management of a chronic cutaneous inflammatory condition. Int J Mol Sci 2016; 17: 1562.

[5] Liu T , Xiao W , Chen M , et al. Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea. JCI insight 2022; 7: e161870.

[6] Chen Q , Shi X , Tang Y , et al. Association between rosacea and cardiometabolic disease: a systematic review and meta-analysis. J Am Acad Dermatol 2020; 83: 1331- 40.

[7] Chen P , Yang Z , Fan Z , et al. Associations of adherence to Mediterranean-like diet pattern with incident rosacea: a prospective cohort study of government employees in China. Front Nutr 2023; 10: 1092781.

[8] Mousavi SM , Jalilpiran Y , Karimi E , et al. Dietary intake of linoleic acid, its concentrations, and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of prospective cohort studies. Diabetes Care 2021; 44: 2173- 81.

[9] Henderson G , Crofts C , Schofield G . Linoleic acid and diabetes prevention. Lancet Diabetes Endocrinol 2018; 6: 12- 3.

[10] Nava Lauson CB , Tiberti S , Corsetto PA , et al. Linoleic acid potentiates CD8(+) T cell metabolic fitness and antitumor immunity. Cell Metab 2023; 35: 633- 50.e9.

[11] Chalmers RJ , Shuster S . Evening primrose seed oil in ichthyosis vulgaris. Lancet 1983; 1: 236- 7.

[12] Liu M , Li X , Chen XY , et al. Topical application of a linoleic acidceramide containing moisturizer exhibit therapeutic and preventive benefits for psoriasis vulgaris: a randomized controlled trial. Dermatol Ther 2015; 28: 373- 82.

[13] Kaikiri H , Miyamoto J , Kawakami T , et al. Supplemental feeding of a gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12- octadecenoic acid, alleviates spontaneous atopic dermatitis and modulates intestinal microbiota in NC/nga mice. Int J Food Sci Nutr 2017; 68: 941- 51.

[14] Hirabayashi T , Anjo T , Kaneko A , et al. PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis. Nat Commun 2017; 8: 14609.

[15] Takeichi T , Hirabayashi T , Miyasaka Y , et al. SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation. J Clin Invest 2020; 130: 890- 903.

[16] Opálka L , Meyer JM , Ondrejčeková V , et al. ω-O-Acylceramides but not ω-hydroxy ceramides are required for healthy lamellar phase architecture of skin barrier lipids. J Lipid Res 2022; 63: 100226.

[17] Peng L , Chen L , Wan J , et al. Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis. Front Immunol 2023; 14: 1179877.

[18] Töröcsik D , Weise C , Gericke J , et al. Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and nonaffected skin of human atopic dermatitis patients. Exp Dermatol 2019; 28: 177- 89.

[19] Rodrigues HG , Vinolo MA , Sato FT , et al. Oral administration of linoleic acid induces new vessel formation and improves skin wound healing in diabetic rats. PLoS One 2016; 11: e0165115.

[20] Zhang Y , Li Y , Zhou L , et al. Nav1.8 in keratinocytes contributes to ROS-mediated inflammation in inflammatory skin diseases. Redox Biol 2022; 55: 102427.

[21] Kimura I , Ichimura A , Ohue-Kitano R , et al. Free fatty acid receptors in health and disease. Physiol Rev 2020; 100: 171- 210.

[22] Zárate R , El Jaber-Vazdekis N , Tejera N , et al. Significance of long chain polyunsaturated fatty acids in human health. Clin Transl Med. 2017; 6: 25.

[23] Im DS . FFA4 (GPR120) as a fatty acid sensor involved in appetite control, insulin sensitivity and inflammation regulation. Mol Aspects Med 2018; 64: 92- 108.

[24] Shapiro H , Theilla M , Attal-Singer J , et al. Effects of polyunsaturated fatty acid consumption in diabetic nephropathy. Nat Rev Nephrol 2011; 7: 110- 21.

[25] Shih CM , Chen CC , Chu CK , et al. The roles of lipoprotein in psoriasis. Int J Mol Sci 2020; 21: 859.

[26] Myśliwiec H , Baran A , Harasim-Symbor E , et al. Serum fatty acid profile in psoriasis and its comorbidity. Arch Dermatol Res 2017; 309: 371- 80.

[27] Huang Y , Chen G , Liu X , et al. Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry.J Proteome Res 2014; 13: 5715- 23.

[28] S NR , Bender K , Lacey N , et al. The fatty acid profile of the skin surface lipid layer in papulopustular rosacea. Br J Dermatol 2012; 166: 279- 87.

[29] Fujii M , Nakashima H , Tomozawa J , et al. Deficiency of n-6 polyunsaturated fatty acids is mainly responsible for atopic dermatitis-like pruritic skin inflammation in special diet-fed hairless mice. Exp Dermatol 2013; 22: 272- 7.

[30] Farvid MS , Ding M , Pan A , et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation 2014; 130: 1568- 78.

[31] Prottey C , Hartop PJ , Black JG , et al. The repair of impaired epidermal barrier function in rats by the cutaneous application of linoleic acid. Br J Dermatol 1976; 94: 13- 21.

[32] Lovászi M , Mattii M , Eyerich K , et al. Sebum lipids influence macrophage polarization and activation. Br J Dermatol 2017; 177: 1671- 82.

[33] Li X , Yang Q , Zheng J , et al. Efficacy and safety of a topical moisturizer containing linoleic acid and ceramide for mild-to-moderate psoriasis vulgaris: a multicenter randomized controlled trial. Dermatol Ther 2020; 33: e14263.

[34] Fats and fatty acids in human nutrition. Report of an expert consultation. FAO Food Nutr Pap 2010; 91: 1- 166.

[35] Janani C , Ranjitha Kumari BD . PPAR gamma gene-a review. Diabetes Metab Syndr 2015; 9: 46- 50.

[36] Marciano DP , Chang MR , Corzo CA , et al. The therapeutic potential of nuclear receptor modulators for treatment of metabolic disorders: PPARγ, RORs, and Rev-erbs. Cell Metab 2014; 19: 193- 208.

[37] Ramot Y , Mastrofrancesco A , Camera E , et al. The role of PPARγ-mediated signalling in skin biology and pathology: new targets and opportunities for clinical dermatology. Exp Dermatol 2015; 24: 245- 51.

[38] Liu Y , Wang J , Luo S , et al. The roles of PPARγ and its agonists in autoimmune diseases: a comprehensive review. J Autoimmun 2020; 113: 102510.

[39] Tisma VS , Basta-Juzbasic A , Jaganjac M , et al. Oxidative stress and ferritin expression in the skin of patients with rosacea. J Am Acad Dermatol 2009; 60: 270- 6.

[40] Yesilirmak N , Bukan N , Kurt B , et al. Evaluation of ocular and systemic oxidative stress markers in ocular rosacea patients. Invest Ophthalmol Vis Sci 2023; 64: 22.

[41] Zhao H , Zhao H , Li M , et al. Twin defect-rich Pt ultrathin nanowire nanozymes alleviate inflammatory skin diseases by scavenging reactive oxygen species. Redox Biol 2024; 70: 103055.

[42] Vaamonde-García C , Riveiro-Naveira RR , Valcárcel-Ares MN , et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum 2012; 64: 2927- 36.

[43] Nakahira K , Haspel JA , Rathinam VA , et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011; 12: 222- 30.

[44] Xi Q , Cheranov SY , Jaggar JH . Mitochondria-derived reactive oxygen species dilate cerebral arteries by activating Ca2+ sparks. Circ Res 2005; 97: 354- 62.

[45] Narayanan D , Xi Q , Pfeffer LM , et al. Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries. Circ Res 2010; 107: 631- 41.

[46] Mulligan CM , Sparagna GC , Le CH , et al. Dietary linoleate preserves cardiolipin and attenuates mitochondrial dysfunction in the failing rat heart. Cardiovasc Res 2012; 94: 460- 8.

[47] Bennett CF , Latorre-Muro P , Puigserver P . Mechanisms of mitochondrial respiratory adaptation. Nat Rev Mol Cell Biol 2022; 23: 817- 35.

[48] Jamwal S , Blackburn JK , Elsworth JD . PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders. Pharmacol Ther 2021; 219: 107705.

[49] Deng Z , Chen M , Liu Y , et al. A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea. EMBO Mol Med 2021; 13: e13560.

[50] Zhang H , Zhang Y , Li Y , et al. Bioinformatics and network pharmacology identify the therapeutic role and potential mechanism of melatonin in AD and rosacea. Front Immunol 2021; 12: 756550.

RIGHTS & PERMISSIONS

The Author(s). Published by Oxford University Press on behalf of Higher Education Press.