RESUMO
TSH/TSHR signaling plays a role in the regulation of lipid metabolism in adipocytes. However, the precise mechanisms are not known. In the present study, we determined the effect of TSH on fatty acid synthase (FASN) expression, and explored the underlying mechanisms. In vitro, TSH reduced FASN expression in both mRNA and protein levels in mature adipocytes and was accompanied by protein kinase A (PKA) activation, cAMP-response element binding protein (CREB) phosphorylation, as well as extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2 -terminal kinase (JNK) activation. TSH-induced downregulation of FASN was partially abolished by inhibition of PKA and ERK, but not JNK. TSHR and FASN expression in visceral tissue was significantly increased in C57BL/6 mice with diet-induced obesity compared with control animals, whereas thyroid TSHR expression was normal. These findings suggest that activation of TSHR directly inhibits FASN expression in mature adipocytes, possibly mediated by PKA and ERK. In obese animals, this function of TSHR seems to be counteracted. The precise mechanisms need further investigation.
Assuntos
Adipócitos/metabolismo , Ácido Graxo Sintase Tipo I/genética , Obesidade/enzimologia , Receptores da Tireotropina/metabolismo , Tireotropina/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , Proteínas Quinases Dependentes de AMP Cíclico/biossíntese , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/biossíntese , Obesidade/patologia , Fosforilação , RNA Mensageiro/biossíntese , Receptores da Tireotropina/genética , Transdução de Sinais/genética , Glândula Tireoide/metabolismo , Tireotropina/genéticaRESUMO
OBJECTIVES: Cholesterol efflux has been thought to be the main and basic mechanism by which free cholesterol is transferred from extra hepatic cells to the liver or intestine for excretion. Salvianolic acid B (Sal B) has been widely used for the prevention and treatment of atherosclerotic diseases. Here, we sought to investigate the effects of Sal B on the cholesterol efflux in THP-1 macrophages. METHODS: After PMA-stimulated THP-1 cells were exposed to 50 mg/L of oxLDL and [(3)H] cholesterol (1.0 µCi/mL) for another 24 h, the effect of Sal B on cholesterol efflux was evaluated in the presence of apoA-1, HDL2 or HDL3. The expression of ATP binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and liver X receptor-alpha (LXRα) was detected both at protein and mRNA levels in THP-1 cells after the stimulation of Sal B. Meanwhile, specific inhibition of PPAR-γ and LXRα were performed to investigate the mechanism. RESULTS: The results showed that Sal B significantly accelerated apoA-I- and HDL-mediated cholesterol efflux in both dose- and time-dependent manners. Meanwhile, Sal B treatment also enhanced the expression of ABCA1 at both mRNA and protein levels. Then the data demonstrated that Sal B increased the expression of PPAR-γ and LXRα. And the application of specific agonists and inhibitors of further confirmed that Sal exert the function through PPAR-γ and LXRα. CONCLUSION: These results demonstrate that Sal B promotes cholesterol efflux in THP-1 macrophages through ABCA1/PPAR-γ/LXRα pathway.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Benzofuranos/farmacologia , Colesterol/metabolismo , Receptores Nucleares Órfãos/metabolismo , PPAR gama/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteína A-I/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Linhagem Celular , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Lipoproteínas HDL2/metabolismo , Lipoproteínas HDL3/metabolismo , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Nucleares Órfãos/antagonistas & inibidores , Receptores Nucleares Órfãos/genética , PPAR gama/antagonistas & inibidores , PPAR gama/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum.