Peroxisome Proliferator Activated Receptor-gamma P465L Point Mutation in Diabetes and Atherosclerosis

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  • March 22, 2019
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  • Pendse, Avani A.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine, Pathobiology and Translational Science Graduate Program
Abstract
  • The dominant-negative P467L mutation in peroxisome proliferator activated receptor-[gamma] (PPAR[gamma]) was identified in insulin resistant patients with hyperglycemia and lipodystrophy. However, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. I hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, masked by hyperinsulinemia, to retain normal plasma glucose. I introduced in PpargP465L/+ mice, Ins2-Akita mutation that causes islet apoptosis to lower plasma insulin. Unlike Ins2Akita/+ littermates, male PpargP465L/+Ins2Akita/+mice have drastically reduced life-span. PpargP465L/+Ins2Akita/+ females have aggravated hyperglycemia, smaller islets, reduced plasma insulin and impaired insulin sensitivity. Enhanced gluoconeogenesis, due to reduced plasma insulin, in PpargP465L/+Ins2Akita/+ females compared to Ins2Akita/+ littermates, contributes to their fasting hyperglycemia. While liver and skeletal muscles remain sensitive, adipose tissue is resistant to insulin. PpargP465L/+Ins2Akita/+ mice have smaller fat depots composed of larger adipocytes suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia. The increasing prevalence of obesity and insulin resistance and its negative impact on atherosclerotic cardiovascular disease is of major concern. In the second part of my study, I hypothesized that the L/+ mutation will worsen atherosclerosis in Apoe-/- mice. Despite a consistent increase in blood pressure, PPAR[gamma]P465L/+ mutation did not affect plaque size in Apoe-/- mice fed normal chow or high-fat-diet. Gene expression studies revealed significantly increased ABCA-1 and decreased CD-36 in PPAR[gamma]P465L/+;Apoe-/- macrophages compared to Apoe-/- littermates, suggesting reduced lipid accumulation. Cultured PPAR[gamma]P465L/+;Aoe-/- macrophages, had a significant reduction in DiI-labeled-VLDL uptake, compared to Apoe-/- macrophages. It is likely that balance between increased blood pressure with its pro-atherogenic potential and macrophage athero-protective phenotype results in an unchanged plaque. Bone marrow transfer experiments to investigate the role of PPAR[gamma]P465L/+ mutation specifically in the macrophage showed a trend towards decrease in plaque size in mice reconstituted with PPAR[gamma]P465L/+;Apoe-/- macrophages. Thus, I have established the causative link between PPAR[gamma]P465L mutation and insulin resistance phenotype, consolidating the crucial role of PPAR[gamma] in diabetes. PPAR[gamma]P465L mutation, however, does not change the atherosclerotic plaque size in Apoe-/- mice, and warrants further investigation.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy
Advisor
  • Maeda, Nobuyo
Degree granting institution
  • University of North Carolina at Chapel Hill
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