Generation of a liver-specific HDAC7 KO mouse model and effect of selective HDAC inhibitors on cholesterol 7α-hydroxylase gene in mice

Histone deacetylases (HDACs) are involved in the regulation of cholesterol 7alpha-hydroxylase gene (Cyp7a1) transcription in response to bile acids (BA). BA increases the HDAC7 nuclear concentration in hepatocytes and promotes the assembly of a repressor complex on the Cyp7a1 promoter. HDAC inhibitors (HDACi) stimulate Cyp7a1 expression and decrease serum cholesterol in mice. The aim of this work was to better understand the role of HDACs, and in particular HDAC7, in the regulation of Cyp7a1 transcription. As a first approach we decided to generate a conditional liver-specific knock-out of Hdac7 gene( H7Liv-KO) using the Cre-loxP technology. Preliminary experiments indicate that H7LivKO mice were viable but we observed a high degree of variability among animals, probably due to the mixed genetic background. These findings suggest that backcrossing with C57Bl/6J is required in order to achieve offspring with a more homogeneous genetic background. A second approach has been the treatment of wt C57Bl/6J mice with pan (SAHA), class I (MS275) and class II selective (MC1568) HDACi. Preliminary experiments were conducted with mice treated for one week every day (ED) or every other day (EOD) with HDAci. Body weight, food and water consumption, glycemia and cholesterol level have been evaluated and no differences where detected between ED and EOD mice. Gene expression analyses showed that the treatment with the class I HDAC selective inhibitor induced a partial de-repression of Cyp7a1 at transcriptional level, implying a major role of class I HDACs in the regulation of Cyp7a1 gene transcription in vivo. Funding: funded by CARIPLO Foundation 2008.2511 to MC