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 ? (PPAR?). In addition to PPAR? 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 PPAR?, while increasing inflammatory cytokines and insulin resistance. These consequences of obesity-mediated adipocyte dysfunction (decreased PPAR?/adiponectin and increased inflammatory adipokines such as TNF?, 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 PPAR? activity, which may function as an endogenous ligand agonist. We hypothesize that the three protective factors, bilirubin, PPAR? 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 PPAR? that reduces vascular dysfunction.
These studies are aimed at understanding ways to reduce central obesity and reduce fat specific hormonal signals that may cause cardiovascular disease. Bilirubin is the strongest antioxidant produced in the body and elevated levels in adults have been shown to prevent obesity, diabetes and cardiovascular disease. We are investigating how bilirubin reduces obesity, and the fat derived factors that can affect the cardiovascular.
| Adeosun, Samuel O; Gordon, Darren M; Weeks, Mary Frances et al. (2018) Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells. Am J Physiol Renal Physiol 315:F323-F331 |
| Hinds Jr, Terry D; Stec, David E (2018) Bilirubin, a Cardiometabolic Signaling Molecule. Hypertension 72:788-795 |
| Adeosun, Samuel O; Moore, Kyle H; Lang, David M et al. (2018) A Novel Fluorescence-Based Assay for the Measurement of Biliverdin Reductase Activity. React Oxyg Species (Apex) 5:35-45 |
| Weaver, Lauren; Hamoud, Abdul-Rizaq; Stec, David E et al. (2018) Biliverdin reductase and bilirubin in hepatic disease. Am J Physiol Gastrointest Liver Physiol 314:G668-G676 |
| Hamoud, Abdul-Rizaq; Weaver, Lauren; Stec, David E et al. (2018) Bilirubin in the Liver-Gut Signaling Axis. Trends Endocrinol Metab 29:140-150 |
| Sundararaghavan, Vikram L; Binepal, Sivjot; Stec, David E et al. (2018) Bilirubin, a new therapeutic for kidney transplant? Transplant Rev (Orlando) 32:234-240 |
| Sundararaghavan, Vikram L; Sindhwani, Puneet; Hinds Jr, Terry D (2017) Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas? Oncotarget 8:3640-3648 |
| Hinds Jr, Terry D; Hosick, Peter A; Chen, Shujuan et al. (2017) Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPAR?. Am J Physiol Endocrinol Metab 312:E244-E252 |
| Nwaneri, Assumpta C; McBeth, Lucien; Hinds Jr, Terry D (2016) Prostate Cancer in African American Men: The Effect of Androgens and microRNAs on Epidermal Growth Factor Signaling. Horm Cancer 7:296-304 |
| Stec, David E; John, Kezia; Trabbic, Christopher J et al. (2016) Bilirubin Binding to PPAR? Inhibits Lipid Accumulation. PLoS One 11:e0153427 |
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