Antioxidant-PPARalpha interaction and hypertension

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DESCRIPTION (provided by applicant): Obesity is a major public health concern that has led to a worldwide epidemic and is the underlying cause of diabetes, atherosclerosis and cardiovascular disease. Excessive visceral and subcutaneous fat is predictive of vascular disease and associated complications, including vascular dysfunction, insulin resistance and decreased levels of the fat burning nuclear receptor, peroxisome proliferator-activated receptor α (PPARα). In addition to PPARα regulating fatty acid metabolism, it has anti-inflammatory properties in vascular inflammation and atherosclerosis, most likely through induction of adiponectin. Adiponectin is an adipose- specific hormone with anti-inflammatory and vascular protective properties, and its circulating levels are decreased in obesity. Obesity increases oxidative stress by enhancing reactive oxygen species and simultaneously decreases expression and activity of key cytoprotective systems including heme oxygenase (HO) and bilirubin as well as PPARα, while increasing inflammatory cytokines and insulin resistance. These consequences of obesity-mediated adipocyte dysfunction (decreased PPARα/adiponectin and increased inflammatory adipokines such as TNFα, IL-1 and IL-6) may lead to vascular dysfunction, which is a prelude to vascular disease and hypertension. Here we provide novel data that bilirubin activates PPARα activity, which may function as an endogenous ligand agonist. We hypothesize that the three protective factors, bilirubin, PPARα and adiponectin, are inextricably linked forming a functional module and a deficiency in any of these factors within adipocytes leads to adipocyte and vascular dysfunction that is associated with obesity. We will test this model in vitro and in vivo to show that bilirubin has protective ani-obese and anti- diabetic properties that are mediated by PPARα that reduces vascular dysfunction.