Altered global microRNA expression in hepatic stellate cells LX-2 by angiotensin-(1-7) and miRNA-1914-5p identification as regulator of pro-fibrogenic elements and lipid metabolism

Autor(es)

da Silva, Brenda de Oliveira ^{[1, 2]} ; Alberici, Luciane Carla ^[3] ; Ramos, Leticia Ferreira ^[1] ; Silva, Caio Mateus ^[1] ; da Silveira, Marina Bonfogo ^[1] ; Dechant, Carlos R. P. ^[3] ; Friedman, Scott L. ^[4] ; Sakane, Kumiko Koibuchi ^[5] ; Goncalves, Leticia Rocha ^[1] ; Moraes, Karen C. M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista, UNESP, Biosci Inst, Dept Biol, Mol Biol Lab, Rio Claro, SP - Brazil

^[2] Univ Fed Ouro Preto, Nucleo Pesquisa Biol, Ouro Preto, MG - Brazil

^[3] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, Ribeirao Preto, SP - Brazil

^[4] Mt Sinai Sch Med, Dept Med, Div Liver Dis, New York, NY - USA

^[5] Univ Vale do Paraiba, UNIVAP, Inst Res & Dev, Sao Jose Dos Campos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; v. 98, p. 137-155, MAY 2018.
• Citações Web of Science: 2

Resumo

The development of new therapeutic strategies to control or reverse hepatic fibrosis requires thorough knowledge about its molecular and cellular basis. It is known that the heptapeptide angiotensin-(1-7) {[}ang-(1-7)] can reduce hepatic fibrosis and steatosis in vivo; therefore, it is important to uncover the mechanisms regulating its activity and cellular model of investigation. Ang-(1-7) is a peptide of the renin-angiotensin system (RAS), and here we investigated its modulatory effect on the expression pattern of microRNAs (miRNAs) in hepatic stellate cells (HSCs) LX 2, which transdifferentiate into fibrogenic and proliferative cells. We compared the miRNA profiles between quiesced, activated and ang-(1-7)-treated activated HSCs to identify miRNAs that may regulate their transdifferentiation. Thirteen miRNAs were pointed, and cellular and molecular analyses identified miRNA1914-5p as a molecule that contributes to the effects of ang-(1-7) on lipid metabolism and on the pro-fibrotic environment control. In our cellular model, we also analyzed the regulators of fatty acid metabolism. Specifically, miRNA-1914-5p regulates the expression of malonyl-CoA decarboxylase (MLYCD) and phosphatidic acid phosphohydrolase (PAP or Lipin-1). Additionally, Lipin-1 was closely correlated with mRNA expression of peroxisome proliferator-activated receptors (PPAR)-alpha and - gamma, which also contribute to lipid homeostasis and to the reduction of TGF-beta 1 expression. These findings provide a novel link between RAS and lipid metabolism in controlling HSCs activation. (AU)

• Processo FAPESP: 09/07671-2 - Análise mecanística dos processos de indução de hipertrofias cardíacas mediadas por inflamação: estudo funcional da proteína CUGBP2
• Beneficiário: Karen Cristiane Martinez de Moraes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/21186-5 - Redes de interações moleculares reguladas por pequenos RNAs não decodificadores no mecanismo fibrosante hepático e suas modulações pelo peptídeo vasoativo angiotensina-(1-7)
• Beneficiário: Karen Cristiane Martinez de Moraes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/17259-9 - Estudos sobre mecanismos de desacoplamento mitocondriais por ácidos graxos não-esterificados como estratégia de prevenção/tratamento da obesidade
• Beneficiário: Luciane Carla Alberici
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores