| Obesity is associated with numerous comorbidities including chronic low-grade inflammation, metabolic dysregulation, and increased risk of colon cancer. Colon polyps are clusters of cells that continue proliferating, leading to the development of colon adenomas which increase the risk of colon cancer. Obesity increases circulating de novo proinflammatory signaling molecules and growth factors, which influence polyp growth and survival, such as cytokines and oxygenated fatty acid (FA) metabolites referred to as oxylipids. FAs are sequestered into larger complex lipids such as phospholipids (PLs), and phospholipases liberate these esterified FAs for metabolism. Omega-3 (o-3) and omega-6 (o-6) polyunsaturated FAs (PUFAs) are of interest in obesity and cancer research, since PUFAs are substrates for oxygenating enzymes which produce oxylipids. There is a dearth of research using newly developed mass spectrometry (MS)-based lipidomic technologies for the characterization and determination of novel lipid biomarkers of altered metabolism and colon polyp risk. Using cutting-edge methods in tandem mass spectrometry (MS/MS), the plasma lipidome was profiled from 126 Caucasian males that were previously recruited for a cross-sectional study investigating biomarkers of colon polyps. Statistical models were adjusted for cofounding factors such as age and smoking. It was hypothesized that three distinct types of lipidomic markers would emerge from the data: lipids associated with only obesity, lipids associated with both obesity and colon polyps, and lipids associated with colon polyps independent of obesity (i.e., after adjusting statistical models for body mass index (BMI) and waist circumference (WC)). Obesity was associated with distinct PUFA differences in plasma phospholipids (PPLs), such as decreases in linoleic (LA, o-6), eicosapentaenoic (EPA, o-3), and docosahexaenoic acid (DHA, o-3) in lysophospholipids (LPLs) and ether linked phosphatidylcholines (PC); and increases in long chain o-6s in diacyl PLs. Non-esterified plasma PUFA concentrations were similar across BMI and WC. Plasma vicinal diols, oxylipids formed through soluble epoxide hydrolase (sEH) metabolism, were inversely associated with obesity. The oxylipids 5-hydroxyeicosatetraenoic acid (HETE), a 5-lipoxygenase (5LOX) metabolite, and 11-HETE, which is formed from non-enzymatic oxygenation, were both increased in obesity. Specific concentration ranges of these HETEs and vicinal diols were determined to be associated with an increased likelihood of obesity. Results of lipidomic data modeled with colon polyps indicated that no specific PPL was associated with colon polyps in our population. However, PPL % total FA differences were highly associated with colon adenomas. The presence of colon adenomas was associated with lower levels of palmitic acid (PA) in PPL, even after adjusting statistical models for obesity. Similarly, colon polyp type (i.e., hyperplastic or adenoma) was significantly associated with increases in plasma non-esterified 5- and 11-HETE, even after adjusting models for obesity. Since lipids such as 5-HETE and LPLs are ligands for inflammation regulating pathways, therefore, future research should investigate whether these lipids influence colon polyp progression. Taken together, the results reported in this dissertation offer new insight into the underlying biology associated with altered metabolism in obesity and the presence of colon polyps, and the lipids reported herein may be useful as plasma biomarkers of altered metabolism and colon polyps. |
