4.7 Article

PPARα regulates the expression of human arylacetamide deacetylase involved in drug hydrolysis and lipid metabolism

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 199, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115010

Keywords

Arylacetamide deacetylase; Lipid metabolism; Gene regulation; Peroxisome proliferator-activated receptor alpha

Funding

  1. Japan Society for the Promotion of Science [19K07082]
  2. Grants-in-Aid for Scientific Research [19K07082] Funding Source: KAKEN

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This study demonstrated the regulation of human AADAC by PPAR alpha through binding to DR1, and the significance of AADAC in lipid accumulation.
Human arylacetamide deacetylase (AADAC) hydrolyzes various drugs containing an acetyl group, such as ketoconazole and rifampicin. Knowledge about the role of human AADAC in drug metabolism is accumulating, but the regulatory mechanism of its expression has not been elucidated. In mice, it has been suggested that Aadac expression may be regulated by peroxisome proliferator-activated receptor alpha (Ppar alpha). This study examined whether human AADAC is regulated by PPAR alpha, which widely regulates the expression of lipid metabolismrelated genes. In human hepatoma Huh-7 cells, AADAC mRNA and protein levels were significantly increased by treatment with fenofibric acid and WY-14643, PPAR alpha ligands. Knockdown and overexpression of PPAR alpha resulted in decreased and increased expression of AADAC, respectively. Luciferase assays revealed that the direct repeat 1 (DR1) at -193/-181 in the AADAC promoter region is responsible for transactivation by PPAR alpha. Chromatin immunoprecipitation assays revealed the binding of PPAR alpha to DR1. Thus, it was demonstrated that human AADAC is regulated by PPAR alpha through binding to DR1. Oil red O staining showed that overexpression of AADAC in Huh-7 cells suppressed lipid accumulation after treatment with free fatty acids. The suppression was restored by treatment with diisopropyl fluorophosphate, an AADAC inhibitor. The WY-14643-mediated suppression of lipid accumulation was restored by AADAC knockdown. These results suggested that AADAC has a role in suppressing cellular lipid accumulation. In conclusion, this study demonstrated the regulation of human AADAC by PPAR alpha and its significance in lipid accumulation.

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