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Inhibition of apolipoprotein A-I expression by TNF-alpha in HepG2 cells: requirement for c-jun.
Parseghian, Shant; Onstead-Haas, Luisa M; Wong, Norman C W; Mooradian, Arshag D; Haas, Michael J.
Afiliação
  • Parseghian S; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, 63104.
J Cell Biochem ; 115(2): 253-60, 2014 Feb.
Article em En | MEDLINE | ID: mdl-24038215
Tumor necrosis factor alpha (TNF α) signals in part through the mitogen activated protein (MAP) kinase c-jun-N-terminal kinase (JNK). Activation of JNK has been shown to promote insulin resistance and dyslipidemia, including reductions in plasma high-density lipoprotein (HDL) and apolipoprotein A-I (apo A-I). To examine how TNF α-mediated JNK activation inhibits hepatic apo A-I production, the effects of c-jun activation on apo A-I gene expression were examined in HepG2 cells. Apo A-I gene expression and promoter activity were measured by Northern and Western blotting and transient transfection. Transient transfection and siRNA were used to specifically over-express or knockout c-jun, c-jun-N-terminal kinase-1 and -2 (JNK1 and JNK2, respectively) and mitogen-activated protein kinase-4 (MKK4). TNF α-treatment of HepG2 cells induced rapid phosphorylation of c-jun on serine 63. In cells treated with phorbol-12-myristate-13-acetate (PMA), apo A-I gene promoter activity was inhibited and apo A-I mRNA content and apo A-I protein secretion decreased. Likewise, over-expression of JNK1 and JNK2 inhibited apo A-I promoter activity. Over-expression of constitutively active MKK4, an upstream protein kinase that directly activates JNK, also inhibited apo A-I promoter activity, while over-expression of a dominant-negative MKK4 de-repressed apo A-I promoter activity in TNF α-treated cells. Inhibition of c-jun synthesis using siRNA but not a control siRNA prevented TNF α-mediated inhibition of apo A-I. These results suggest that the MKK4/JNK/c-jun signaling pathway mediates TNF α-dependent inhibition of apo A-I synthesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator de Necrose Tumoral alfa / Apolipoproteína A-I / Proteína Quinase 8 Ativada por Mitógeno / Proteína Quinase 9 Ativada por Mitógeno Limite: Humans Idioma: En Revista: J Cell Biochem Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator de Necrose Tumoral alfa / Apolipoproteína A-I / Proteína Quinase 8 Ativada por Mitógeno / Proteína Quinase 9 Ativada por Mitógeno Limite: Humans Idioma: En Revista: J Cell Biochem Ano de publicação: 2014 Tipo de documento: Article