Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: A common pathway to the ABCA1 gene regulation

Expression of the activator protein (AP) 2β is closely associated with type-2 diabetes and negatively regulates expression of the adiponectin gene. We previously demonstrated that AP-2α negatively regulates the ATP-binding cassette A1 (ABCA1) gene through its Ser-phosphorylation by protein kinase (PK) D. The phosphorylation site of AP-2α located in the basic domain, a critical site for its DNA binding, is conserved among species and five subtypes of AP-2. We therefore investigated the involvement of PKD in regulation of the adiponectin gene expression. Knockdown of PKD by its siRNA led to the increase in the mRNA and the promoter activity of adiponectin, and resulted in increase of adiponectin secretion and decrease of fat accumulation in cultured cells. PKD activators decreased expression of the adiponectin gene, and its inhibition by PKD siRNA and by a selective inhibitor Gö6983 canceled this effect. ChIP analysis demonstrated that inhibition of PKD activity decreased the DNA binding of AP-2β to the adiponectin promoter. Finally, Gö6983 increased adiponectin expression in mice. PKD is thus a common modulator of the DNA binding activity of AP-2α and AP-2β through their phosphorylation for negative regulation of the ABCA1 and adiponectin genes expression, respectively.