Obesity is a significant contributor to cardiometabolic diseases including hypertension, non-alcoholic fatty liver disease (NAFLD) and type II diabetes. All of these conditions contribute to the increased morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and development of cardiovascular disease and metabolic disorders including NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against cardiometabolic disease is not known. We have exciting data demonstrating for the first time that bilirubin signals through nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPARa) to protect against cardiometabolic disorders. In addition, bilirubin can also inactivate glycogen synthase kinase-3b (GSK3b) to increase PPARa target genes such as fibroblast growth factor 21 (FGF21); however, the specific roles of GSK3b inactivation/PPARa activation to the anti-hypertensive, anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia are not known. Biliverdin reductase (BVR) is the enzyme responsible for reduction of biliverdin to bilirubin. It can generate bilirubin found in the plasma and generated inside the cell. The goal of this proposal is to test the central hypothesis that bilirubin and BVRA protect against obesity-induced hepatic steatosis, insulin resistance and hypertension via activation of the PPARa signaling axis.
Aim 1 will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 lowers blood pressure and reverses dietary obesity-induced hepatic steatosis and hepatic insulin resistance. Aim 2 will test the hypothesis that moderate hyperbilirubinemia lowers blood pressure and reverses hepatic steatosis and insulin resistance via activation of PPARa. Aim 3 will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3b mediated pathway that decreases PPARa activity.
Findings of these studies will have profound implications on development of moderate hyperbilirubinemia as a novel therapy for treatment of obesity-induced cardiometabolic disease. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in protection against obesity-induced cardiometabolic diseases such as hypertension, NAFLD and type II diabetes.
Diabetes mellitus (DM) is one of the leading risk factors for cerebrovascular disease (CVD) and cognitive impairment, especially at the late stage with mild hypertension, but the underlying mechanisms have not been fully elucidated. Dementia is one of the major causes of disability, and the fifth leading cause of death in the elderly in the US. The annual cost for treating dementia is $159 billion, and is projected to rise to $511 billion by 2040. There is an urgent need to understand the mechanisms involved and for development of new therapeutic strategies to delay the onset and progression of these devastating diseases. Mounting evidence suggests that DM is associated with impaired endothelial function and neurovascular coupling, and elevated myogenic tone and reactivity at an early stage. The enhanced myogenic tone and activity in DM decline with age, however, it is to be determined whether CBF autoregulation is impaired in vivo and if it plays a role in the development of dementia in hypertensive DM.
This proposal builds upon our preliminary data indicating that the myogenic response and CBF autoregulation are impaired in response to elevated cerebral perfusion pressure in our novel diabetic rat models. Following development of mild hypertension, DM rats exhibit BBB leakage, inflammation, vascular remodeling, neurodegeneration and cognitive dysfunction. Importantly, forced dilatation of middle cerebral artery (MCA) and CBF autoregulatory breakthrough occurring at lower pressure are only observed in older DM rats with long standing hyperglycemia and after they have developed mild hypertension. We also observed that the neurodegeneration is associated with elevated expression of beta amyloid (Aβ 1-42) and pTau (S416) in the brain in mild hypertensive DM rats, suggesting that Alzheimer-like neuronal cell death pathways are also activated. The enhanced expression of GFAP and IL-1β in hypertensive DM rats indicate that glial activation and inflammation may play a role in linking aging, diabetes and cognitive deficits. In translational studies, we found that cognitive impairment in elderly participants in a largely diabetic ARIC-NCS population may be associated with impaired CBF autoregulation.
This proposal will use our novel non-obese types 1 and 2 DM rat models, which do not exhibit severe lipid and other metabolic derangements normally associated with DM, to investigate whether impaired myogenic response and CBF autoregulation contribute to cognitive impairment, and whether the synergistic effects of DM and hypertension promote development of cognitive deficits. We will also use luseogliflozin to normalize plasma glucose levels by inhibition of renal sodium-glucose co-transporter 2 (SGLT2) without altering blood pressure in our DM models, as we previously reported, to determine the role of hyperglycemia in cerebral vascular dysfunction and dementia. This proposal will address one of the significant gaps in this field by investigating whether chronic hyperglycemia, especially in association with hypertension, causes impairment of CBF autoregulation and dementia using our novel diabetic rat models.
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder characterized by a loss of immunological tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. The immune system dysfunction in SLE leads to downstream chronic inflammation and high rates of hypertension, renal injury, and cardiovascular disease. Patients with SLE also have alterations in circulating cytokines, including elevated plasma levels of the adipokine leptin. Leptin is produced by white adipose tissue and has a prominent role in regulating appetite and energy expenditure via its actions in the hypothalamus. However, it also plays a key role in the maintenance and development of inflammation, in part through its direct effects on cells of both the innate and adaptive immune systems.
The central goal of this project is to examine the contribution of leptin mediated immune system activation on the pathogenesis of hypertension in SLE. To accomplish this goal, a clinically relevant model of SLE, the female NZBWF1 mouse, will be utilized. Similar to patients with SLE, the NZBWF1 mouse exhibits hypertension, renal injury, and elevated circulating leptin levels, in addition to prominent immune system dysfunction. Work in animal models of autoimmunity strongly implicate leptin in the pathogenesis of autoimmune disease, but the contribution of leptin to the prevalent hypertension during SLE, and the mechanism by which this occurs is unknown. Thus, specific aim 1 will test the hypothesis that elevated leptin during SLE promotes hypertension by stimulating the expansion of proinflammatory TH1 and TH17 cells and decreasing TREG cells. Specific aim 2 will test the hypothesis that elevated leptin during SLE leads to the development of hypertension by promoting B cell survival and the production of autoantibodies.
To accomplish these aims, we will administer leptin or block leptin signaling, and test the impact on the development of B and T lymphocyte dysfunction and autoimmune-associated hypertension. Because leptin acts both centrally (central nervous system) and peripherally, we will also examine relative contribution of central and peripheral leptin on immune system function.