RESUMEN
SMILE (small heterodimer partner-interacting leucine zipper protein) is a transcriptional corepressor that potently regulates various cellular processes such as metabolism and growth in numerous tissues. However, its regulatory role in skin tissue remains uncharacterized. Here, we demonstrated that SMILE expression markedly decreased in human melanoma biopsy specimens and was inversely correlated with that of microphthalmia-associated transcription factor (MITF). During melanogenesis, α-melanocyte-stimulating hormone (α-MSH) induction of MITF was mediated by a decrease in SMILE expression in B16F10 mouse melanoma cells. Mechanistically, SMILE was regulated by α-MSH/cAMP/protein kinase A signaling and suppressed MITF promoter activity via corepressing transcriptional activity of the cAMP response element-binding protein. Moreover, SMILE overexpression significantly reduced α-MSH-induced MITF and melanogenic genes, thereby inhibiting melanin production in melanocytes. Conversely, SMILE inhibition increased the transcription of melanogenic genes and melanin contents. These results indicate that SMILE is a downstream effector of cAMP-mediated signaling and is a critical factor in the regulation of melanogenic transcription; in addition, they suggest a potential role of SMILE as a corepressor in skin pigmentation.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Melanoma , Factor de Transcripción Asociado a Microftalmía , Animales , Humanos , Ratones , alfa-MSH/farmacología , alfa-MSH/metabolismo , Línea Celular Tumoral , AMP Cíclico/metabolismo , Melaninas/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Monofenol Monooxigenasa/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genéticaRESUMEN
A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.
Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Hígado Graso/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Autofagia , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/fisiología , Línea Celular Tumoral , Dieta Alta en Grasa/efectos adversos , Hígado Graso/fisiopatología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos/fisiología , Lípidos/fisiología , Lipogénesis , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Transducción de Señal/fisiología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/fisiología , Triglicéridos/metabolismoRESUMEN
SCOPE: Obesity and diabetes are major public health problems and are emerging as pandemics. Considerable evidence suggests that pear fruit consumption is associated with a lower risk of obesity-related complications. Thus, the present study is conducted to investigate the therapeutic potential of pear extract (PE) for reversing obesity and associated metabolic complications in high-fat diet-induced obese mice. METHODS AND RESULTS: Obesity is induced in male C57BL/6 mice fed a high-fat diet for 11 weeks. After the first 6 weeks on the diet, obese mice are administered vehicle or PE for 5 weeks. PE treatment decreases body weight gain, expands white adipose tissue (WAT), and causes hepatic steatosis in obese mice, as well as inhibits adipogenesis and lipogenesis. Impaired glucose tolerance and insulin resistance are improved by PE. In addition, PE reduces macrophage infiltration and expression of pro-inflammatory genes and deactivates mitogen-activated protein kinases in WAT. Finally, malaxinic acid is identified as an active component responsible for the anti-obesity effects of PE in mice. CONCLUSION: The results demonstrate that PE supplementation ameliorates diet-induced obesity and associated metabolic complications and suggest the health-beneficial effects of both pear fruits and malaxinic acid in counteracting these diseases.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Benzoatos/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/dietoterapia , Paniculitis/dietoterapia , Extractos Vegetales/farmacología , Piranos/uso terapéutico , Pyrus/química , Adipogénesis/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Animales , Fármacos Antiobesidad/farmacología , Benzoatos/farmacología , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/etiología , Paniculitis/etiología , Paniculitis/patología , Extractos Vegetales/análisis , Polifenoles/análisis , Piranos/farmacología , Aumento de Peso/efectos de los fármacosRESUMEN
Despite the critical role of melanin in the protection of skin against UV radiation, excess production of melanin can lead to hyperpigmentation and skin cancer. Pear fruits are often used in traditional medicine for the treatment of melasma; therefore, we investigated the effects of pear extract (PE) and its component, protocatechuic acid (PCA), on melanogenesis in mouse melanoma cells. We found that PE and PCA significantly suppressed melanin content and cellular tyrosinase activity through a decrease in the expression of melanogenic enzymes and microphthalmia-associated transcription factor (Mitf) in α-melanocyte stimulating hormone-stimulated mouse melanoma cells. Moreover, PCA decreased cyclic adenosine monophosphate (cAMP) levels and cAMP-responsive element-binding protein phosphorylation, which downregulated Mitf promoter activation and subsequently mediated the inhibition of melanogenesis. These results suggested that pear may be an effective skin lightening agent that targets either a tyrosinase activity or a melanogenic pathway.