RESUMEN
Fats are essential in healthy diets, but how dietary fats affect immune cell function and overall health is not well understood. Mimicking human high-fat diets (HFDs), which are rich in different fatty acid (FA) components, we fed mice various HFDs from different fat sources, including fish oil and cocoa butter. Mice consuming the fish oil HFD exhibit a hair-loss phenotype. Further studies show that omega-3 (n-3) FAs in fish oil promote atypical infiltration of CD207- (langerin-) myeloid macrophages in skin dermis, which induce hair loss through elevated TNF-α signaling. Mechanistically, epidermal fatty acid binding protein (E-FABP) is demonstrated to play an essential role in inducing TNF-α-mediated hair loss by activating the n-3 FA/ROS/IL-36 signaling pathway in dermal resident macrophages. Absence of E-FABP abrogates fish oil HFD-induced murine hair loss. Altogether, these findings support a role for E-FABP as a lipid sensor mediating n-3 FA-regulated macrophage function and skin health.
Asunto(s)
Ácidos Grasos Omega-3 , Aceites de Pescado , Ratones , Humanos , Animales , Aceites de Pescado/farmacología , Aceites de Pescado/metabolismo , Dieta Alta en Grasa/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo , Grasas de la Dieta/farmacología , Macrófagos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/metabolismo , Alopecia/metabolismoRESUMEN
The most recent American Dietary Guidelines (2020-2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high-fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired antitumor T-cell responses by promoting naïve T-cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial reactive oxygen species production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T-cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP-mediated T-cell dysfunction. SIGNIFICANCE: These findings suggest that modulation of dietary oil composition and inhibition of E-FABP activity may represent novel strategies to enhance T-cell function in the prevention and treatment of obesity-associated cancers.
Asunto(s)
Grasas de la Dieta/toxicidad , Proteínas de Unión a Ácidos Grasos/metabolismo , Ácidos Linoleicos/toxicidad , Neoplasias Mamarias Experimentales/patología , Mitocondrias/patología , Linfocitos T/inmunología , Animales , Proteínas de Unión a Ácidos Grasos/genética , Femenino , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Obesidad/fisiopatología , Linfocitos T/efectos de los fármacos , Delgadez/fisiopatologíaRESUMEN
There is an urgent need to investigate the potential targeted therapy approach for triple-negative breast cancer (TNBC). Our present study reveals that histone deacetylase inhibitors (HDACIs) suberoyl anilide hydroxamic acid (SAHA) and sodium butyrate (NaB) significantly inhibit cell proliferation, arrest cell cycle at G0/G1 phase, and induce mitochondrial related apoptosis of TNBC cells. Further, SAHA and NaB decrease the phosphorylation, protein and mRNA levels of mutant p53 (mtp53) in TNBC cells. While SAHA or NaB has no similar inhibition effect on wild type p53 (wtp53). The inhibition apparently occurs at the level of transcription because the down regulation of precursor p53 transcription is much more rapid (less than 2h) and sharp than that of mature p53. The knockdown of HDAC8, while not HDAC6, inhibits the transcription of mtp53 in TNBC cells. The luciferase assay and ChIP analysis reveal that both SAHA and NaB can reduce the binding of transcription factor Yin Yang 1 (YY1) with the -102 to -96 position of human p53 promoter. Knockdown of YY1 also significantly inhibits the transcription of mtp53 in TNBC cells. Further, SAHA and NaB can inhibit the association of HDAC8 and YY1, increase acetylation of residues 170-200 of YY1, then decrease its transcription activities, and finally suppress YY1 induced p53 transcription. Together, our data establish that SAHA and NaB can be considered as drug candidates for TNBC patients, and HDAC8/YY1/mtp53 signals act as an important target for TNBC treatment.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Proteínas Represoras/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína p53 Supresora de Tumor/genética , Factor de Transcripción YY1/metabolismo , Apoptosis , Ácido Butírico/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Histona Desacetilasas/genética , Humanos , Ácidos Hidroxámicos/farmacología , Mitocondrias/efectos de los fármacos , Mutación , Proteínas Represoras/genética , Transducción de Señal , Transcripción Genética , Neoplasias de la Mama Triple Negativas/enzimología , Proteína p53 Supresora de Tumor/metabolismo , Vorinostat , Factor de Transcripción YY1/genéticaRESUMEN
OBJECTIVE: To investigate NF-kappaB and IkappaBalpha activities in HL-60 induced by TNF-alpha in order to understand the molecular mechanism of GbE in asthma treatment. METHODS: The amount of IkappaBalpha in HL-60 cells stimulated by TNF-alpha and GbE was measured by western blotting. Plasmid pNF-kappaB-LuC was transfected and NF-kappaB activity was analyzed by measuring the expression level of luciferase. RESULTS: It showed in the luciferase assay that the activity of NF-kappaB could significantly be suppressed in HL-60 cells after the pretreatment with CGbE. However, the phosphorylation and subsequent degradation of IKBalpha induced by TNF-alpha can not be inhibited in HL-60 cells even we prolonged the treatment time or increased the concentration of GhE. CONCLUSION: GhE can suppress the NF-kappaB gene expression actively on independent of NIK/ IKK/ IkappaBalpha pathway in HL-60 cells.