Desaturation of sebaceous‐type saturated fatty acids through the <scp>SCD1</scp> and the <scp>FADS2</scp> pathways impacts lipid neosynthesis and inflammatory response in sebocytes in culture

Flori, Enrica; Mastrofrancesco, Arianna; Ottaviani, Monica; Maiellaro, Miriam; Zouboulis, Christos C.; Camera, Emanuela

doi:10.1111/exd.14780

Cited by 2 publications

(1 citation statement)

References 71 publications

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“…35,36 Most of the BCFAs were decreased in severe AD in both females and males, while 12Me-C14:0, 13Me-C16:0 In Table S3 (Appendix S2), we evaluate the extent of lipid transformation processes occurring in the SG. We focused on specific FFAs ratios expressing the FADS2, 37,38 the SCD1 39 and the elongation activity, 40,41 and their contribution to the formation of complex lipids. C18:2 PUFA was examined separately.…”

Section: Anova-simultaneous Component Analysis (Asca) On the Relative...mentioning

confidence: 99%

Biosignatures of defective sebaceous gland activity in sebum‐rich and sebum‐poor skin areas in adult atopic dermatitis

Cavallo,

Camera,

Bottillo

et al. 2024

Experimental Dermatology

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Atopic dermatitis (AD) is a composite disease presenting disruption of the skin permeability barrier (SPB) in the stratum corneum (SC). Recent evidence supports derangement of the sebaceous gland (SG) activity in the AD pathomechanisms. The objective of this study was to delineate profiles of both sebaceous and epidermal lipids and of aminoacids from SG‐rich (SGR) and SG‐poor (SGP) areas in AD. Both sebum and SC were sampled from SGR areas, while SC was sampled also from SGP areas in 54 adult patients with AD, consisting of 34 and 20 subjects, respectively with and without clinical involvement of face, and in 44 age and sex‐matched controls. Skin biophysics were assessed in all sampling sites. Disruption of the SBP was found to be associated with dysregulated lipidome. Abundance of sapienate and lignocerate, representing, respectively, sebum and the SC type lipids, were decreased in sebum and SC from both SGR and SGP areas. Analogously, squalene was significantly diminished in AD, regardless the site. Extent of lipid derangement in SGR areas was correlated with the AD severity. The abundance of aminoacids in the SC from SGR areas was altered more than that determined in SGP areas. Several gender‐related differences were found in both controls and AD subgroups. In conclusion, the SG activity was differently compromised in adult females and males with AD, in both SGR and SGP areas. In AD, alterations in the aminoacidome profiles were apparent in the SGR areas. Lipid signatures in association with aminoacidome and skin physical properties may serve the definition of phenotype clusters that associate with AD severity and gender.

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Section: Anova-simultaneous Component Analysis (Asca) On the Relative...mentioning

confidence: 99%

Biosignatures of defective sebaceous gland activity in sebum‐rich and sebum‐poor skin areas in adult atopic dermatitis

Cavallo,

Camera,

Bottillo

et al. 2024

Experimental Dermatology

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Aramchol attenuates fibrosis in mouse models of biliary fibrosis and blocks the TGFβ-induced fibroinflammatory mediators in cholangiocytes

Aseem,

Way,

Wang

et al. 2024

Preprint

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Background: Fibroinflammatory cholangiopathies, such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), are characterized by biliary fibrosis and inflammation, driving disease-related complications. In biliary fibrosis, cholangiocytes activated by transforming growth factor-β (TGFβ) communicate with immune cells and activate hepatic myofibroblasts to deposit the extracellular matrix (ECM). TGFβ may regulate stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, in stimulating fibroinflammatory lipid signaling. However, the role of SCD or its inhibitor, Aramchol, has not been investigated in biliary fibrosis or TGFβ-mediated cholangiocyte activation. Method: 10--16-week-old multi-drug resistance 2 knockout (Mdr2-/-) and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were orally gavaged daily with Aramchol at 12.5 mg/kg/day for 4 and 3 weeks, respectively. Liver and serum were harvested for the assessment of fibrosis and inflammation. Transformed human cholangiocyte cells (H69) and mouse large biliary epithelial cells (MLEs) were used to test the effects of the SCD inhibitor, Aramchol, at varying doses on TGFβ-mediated expression of fibroinflammatory signals and were confirmed in PSC-derived cholangiocytes (PSC-Cs) using ELISA, qPCR, and Western blot analyses. Results: Aramchol treatment of Mdr2-/- mice with established biliary fibrosis (treatment) and DDC diet-induced (prevention) models of cholestatic injury and fibrosis demonstrated significant reductions in both measures of ECM synthesis (mRNA expression of ECM components in the liver), collagen content of the liver (picrosirius red staining and hydroxyproline content) and myofibroblast activation (αSMA staining). Il6 and Tnfa were also reduced with Aramchol in the liver. RNA-seq analysis of H69 cells showed that Aramchol co-treatment led to significant inhibition of TGFβ-induced hepatic fibrosis pathways while upregulating peroxisome proliferator-activated receptor (PPAR) signaling. SCD expression was significantly increased in TGFβ-treated H69 cells (2-fold, p<0.05). Aramchol in a dose-dependent manner significantly attenuated the increased expression of the fibrotic marker, plasminogen activator inhibitor-1 (PAI-1/SERPINE1), and hepatic stellate cell-activating genes (VEGFA and PDGFB) in TGFβ-activated H69 and MLEs. Aramchol also markedly reduced the expression of the inflammatory cytokine, interleukin 6 (IL6). SCD siRNA knockdown produced similar results in H69 cells. Furthermore, in PSC-Cs, the expressions of SCD, VEGFA and IL6 were significantly reduced with Aramchol. The expression of the anti-fibroinflammatory factors PPARα and -γ were modestly increased in cholangiocyte cell lines with increased expression of PPAR-responsive genes and increased nuclear binding of DNA PPAR response elements with Aramchol co-treatment compared to TGFβ only. Conclusion: Aramchol, an SCD inhibitor, both attenuates and prevents biliary fibrosis in mouse models of cholestatic injury and fibrosis. This effect is partially due to Aramchol inhibiting TGFβ-induced fibroinflammatory mediators in cholangiocytes by upregulating PPARα and -γ expression and activity. These findings, along with Aramchol's excellent safety profile in clinical trials, provide the rationale for assessing Aramchol in further clinical studies in patients with biliary fibrosis, particularly PSC, where a treatment is desperately needed.

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Desaturation of sebaceous‐type saturated fatty acids through the SCD1 and the FADS2 pathways impacts lipid neosynthesis and inflammatory response in sebocytes in culture

Cited by 2 publications

References 71 publications

Biosignatures of defective sebaceous gland activity in sebum‐rich and sebum‐poor skin areas in adult atopic dermatitis

Biosignatures of defective sebaceous gland activity in sebum‐rich and sebum‐poor skin areas in adult atopic dermatitis

Aramchol attenuates fibrosis in mouse models of biliary fibrosis and blocks the TGFβ-induced fibroinflammatory mediators in cholangiocytes

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