The human liver fatty acid binding protein (FABP1) gene is activated by FOXA1 and PPARa; and repressed by C/EBPa: Implications in FABP1 down-regulation in nonalcoholic fatty liver disease

Autor: Guzmán C, Benet M, Pisonero-Vaquero S, Moya M, García-Mediavilla MV, Martínez-Chantar ML, González-Gallego J, Castell JV, Sánchez-Campos S, Jover R
Rok vydání: 2013
Zdroj: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
ISSN: 0925-4439
Popis: Liver fatty acid binding protein (FABP1) prevents lipotoxicity of free fatty acids and regulates fatty acid trafficking and partition. Our objective is to investigate the transcription factors controlling the human FABP1 gene and their regulation in nonalcoholic fatty liver disease (NAFLD). Adenovirus-mediated expression of multiple transcription factors in HepG2 cells and cultured human hepatocytes demonstrated that FOXA1 and PPARa are among the most effective activators of human FABP1, whereas C/EBPa is a major dominant repressor. Moreover, FOXA1 and PPARa induced re-distribution of FABP1 protein and increased cytoplasmic expression. Reporter assays demonstrated that the major basal activity of the human FABP1 promoter locates between -96 and -229bp, where C/EBPa binds to a composite DR1-C/EBP element. Mutation of this element at -123bp diminished basal reporter activity, abolished repression by C/EBPa and reduced transactivation by HNF4a. Moreover, HNF4a gene silencing by shRNA in HepG2 cells caused a significant down-regulation of FABP1 mRNA expression. FOXA1 activated the FABP1 promoter through binding to a cluster of elements between -229 and -592bp, whereas PPARa operated through a conserved proximal element at -59bp. Finally, FABP1, FOXA1 and PPARa were concomitantly repressed in animal models of NAFLD and in human nonalcoholic fatty livers, whereas C/EBPa was induced or did not change. We conclude that human FABP1 has a complex mechanism of regulation where C/EBPa displaces HNF4a and hampers activation by FOXA1 and PPARa. Alteration of expression of these transcription factors in NAFLD leads to FABP1 gen repression and could exacerbate lipotoxicity and disease progression.
Databáze: OpenAIRE
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