Mechanisms Regulating Repression of Haptoglobin Production by Peroxisome Proliferator-Activated Receptor-γ Ligands in Adipocytes

Obesity leads to inflammation of white adipose tissue involving enhanced secretion of cytokines and acute-phase proteins in response in part to the accumulation of excess lipids in adipocytes. Haptoglobin is an acute-phase reactant secreted by white adipose tissue and induced by inflammatory cytokines such as TNF alpha. In this study, we investigated the mechanisms regulating haptoglobin expression in adipocytes. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists such as thiazolidinediones (TZDs) as well as non-TZD ligands can repress in vitro and in vivo haptoglobin expression in adipocytes and also prevent its induction by TNF alpha. This action requires direct involvement of PPAR gamma in regulating haptoglobin gene transcription because mutation of critical amino acids within helix 7 of the ligand-binding domain of PPAR gamma prevents repression of the haptoglobin gene by the synthetic ligands. Chromatin immunoprecipitation analysis shows active binding of PPAR gamma to a distal region of the haptoglobin promoter, which contains putative PPAR gamma binding sites. Additionally, PPAR gamma induces transcription of a luciferase reporter gene when driven by the distal promoter region of the haptoglobin gene, and TZD treatment significantly reduces the extent of this induction. Furthermore, the mutated PPAR gamma is incapable of enhancing luciferase activity in these in vitro reporter gene assays. In contrast to other adipokines repressed by TZDs such as resistin and chemerin, repression of haptoglobin does not require either CCAAT/enhancer-binding protein C/EBP alpha or the corepressors C-terminal binding protein 1 or 2. These data are consistent with a model in which synthetic PPAR gamma ligands selectively activate PPAR gamma bound to the haptoglobin gene promoter to arrest haptoglobin gene transcription. (Endocrinology 151: 586-594, 2010)