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Specific Overexpression of Mitofusin-2 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in Mice Model.
Hum Gene Ther ; 31(1-2): 103-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802713
ABSTRACT
Liver fibrosis is a chronic liver disease that could further develop to cirrhosis and liver carcinoma. Hepatic stellate cells (HSCs) are primary effector cells to initiate liver fibrosis. We aimed to explore the function and underlying mechanisms of mitochondrial fusion protein Mitofusin-2 (MFN2) in liver fibrosis. First, we utilized an alpha-smooth muscle actin promoter to overexpress MFN2 specifically in HSCs using adeno-associated virus (AAV) vector (AAV-MFN2). Overexpression of MFN2 was specifically achieved in HSC-T6 cells, but not in murine bone marrow-derived macrophages or hepatocyte AML-12 cells. We found that high expression of MFN2 induced apoptosis of HSC-T6 cells. Mechanistically, we demonstrated that high level of MFN2 inhibited TGF-ß1/Smad signaling pathway, triggered downregulation of type I, type III, and type IV collagen, and antagonized the formation of factors associated with liver fibrosis. Furthermore, we found that overexpression of MFN2 using AAV-MFN2 ameliorated CCl4-induced liver fibrosis in vivo with significantly decreased immune cell infiltration. Taken together, our findings indicate that MFN2 is critical in regulating apoptosis and liver fibrosis in HSCs, which might be a useful therapeutic target to treat liver fibrosis.

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Idioma: Inglês Revista: Hum Gene Ther Assunto da revista: Genética Médica / Terapêutica Ano de publicação: 2020 Tipo de documento: Artigo