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Indiana University-Purdue University Indianapolis (IUPUI) / The incidence of Metabolic Syndrome (MetS) is increasing worldwide and accompanied by elevated risks for cardiovascular disease (CVD) and other subsequent comorbidities. MetS is associated with increased circulating triglycerides. A key enzyme involved in triglyceride (TG) clearance is lipoprotein lipase (LPL) whose activity is modulated by a variety of factors. Recent literature has identified the importance of angiopoietin-like proteins (ANGPTL) as regulators of LPL activity and has hypothesized a model in which three of these proteins interact with LPL to regulate the partitioning of TG metabolism from adipose to skeletal muscle. The work detailed in this dissertation adds to the model of ANGPTL regulation of LPL by establishing how ANGPTL8 modulates the ability of ANGPTL3 and ANGPTL4 to inhibit LPL activity in the bloodstream and localized environments, respectively. In the updated model, elevated insulin concentrations result in increased hepatic ANGPTL3/8 secretion and increased ANGPTL4/8 in adipose tissue. ANGPTL3/8 works as an endocrine molecule to inhibit skeletal muscle LPL from hydrolyzing circulating TG. Simultaneously, ANGPTL4/8 works in a paracrine mechanism to bind LPL on the endothelial vasculature adjacent to adipose tissue to alleviate ANGPTL4-mediated LPL inhibition and also prevent ANGPTL3/8 inhibition of localized LPL. Thus, in the postprandial state free fatty acids (FFA) from the hydrolysis of TG are directed into adipocytes for storage. Under fasting conditions, ANGPTL8 production is decreased in adipocytes and hepatocytes. This decreased production results in diminished ANGPTL4/8 and ANGPTL3/8 secretion from their respective tissues. As a result, ANGPTL4 inhibits adipocyte localized LPL activity while ANGPTL3 at physiological concentrations has minimal effect on LPL activity. Furthermore, any ANGPTL3/8 which is produced has its LPL-inhibitory ability diminished by the circulating apolipoprotein ApoA5. LPL is more active in skeletal muscle compared to adipose tissue where energy is shunted towards utilization in the muscle and away from storage in adipose tissue. A complete understanding of LPL regulation by ANGPTL proteins can potentially provide therapeutics targets for MetS.

Stroke is the third leading cause of death and the most common cause of disabilities worldwide. Apolipoprotein A5 gene (APO A5), which encodes a 369 amino acid protein called Apolipoprotein AV (apo AV), has several single nucleotide polymorphisms (SNPs) found to be associated with altered triglyceride (TG) levels. Atherosclerosis is a major cause of ischemic stroke and this pathology may be associated with variability of TG levels. The main objective of this study was to investigate the coding region (c.553G&gt / T) and promoter region (-1131T/C) polymorphisms of the APO A5 gene as a risk factor for ischemic stroke. The study group in Turkish population consisted of 198 unrelated ischemic stroke patients and 130 control subjects. There was no statistically significant difference between the groups with respect to age and gender. Total blood samples were obtained from G&uuml / lhane Military Medical Academy Hospital, Neurology Department, Ankara. In stroke patients, hypertension and diabetes were 2.5 times more common and high-density lipoprotein cholesterol (HDL-C) was significantly lower than controls. Logistic regression analysis showed that hypertension, diabetes and smoking were significant predictors of stroke. The frequency of risky alleles c.553T and -1131C were 0.003 and 0.098, respectively, in patients and were nearly the same with controls. The risk of hypertensive and diabetic individuals having ischemic stroke was higher in -1131C allele carriers (Odds ratio / OR= 3.4 and 6.4, respectively) than -1131TT individuals (OR= 2.3 and 1.9, respectively). Stroke patients with -1131C allele had significantly higher TG levels (1.70 mmol/L) and lower HDL-C levels (1.05 mmol/L) when compared to controls (1.35 mmol/L and 1.20 mmol/L, respectively) with the same genotype. Logistic regression analysis revealed elevated TG level to be associated with 2.2-fold and low levels of HDL-C to be associated with 1.8-fold increase in the risk of ischemic stroke versus control status. This is the first study investigating the relation between APO A5 c.553G&gt / T polymorphism and stroke risk. Additionally, in Turkish population -1131T/C polymorphism was analyzed for the first time in terms of its relation to ischemic stroke. The present study demonstrated that the frequency of risky alleles c.553T and-1131C were nearly the same in stroke patients and control subjects. Consequently, we decided that carrying minor alleles of c.553G&gt / T and-1131T/C polymorphisms do not constitute a risk for ischemic stroke.