Secretin, the first hormone commencing the field of endocrinology, has been studied for its pleiotropic role in the body inclusive of its neuroactive and body water homeostatic and gastrointestinal functions. Yet, the metabolic effect of secretin remains elusive and is being proposed recently for a revisit. Recent discovery from our lab showed an anorectic response for secretin, while its role in lipid homeostasis remains largely unexplored. Exerting functions such as exocrine pancreatic secretion and gastric motility inhibition, intestinal fatty acid induced release of secretin was recently shown to be mediated by CD36. Fasting related increase in plasma secretin concentration has been proposed to be involved in lipolysis but evidences regarding lipolytic actions of secretin remain contradictory. Recent report has suggested that secretin stimulates both lipolysis and lipogenesis in adipose cells. Thus, we hypothesize that secretin modulates lipid homeostasis, which was examined under two opposite, energy deficient and energy excess, conditions. Under energy deficient/starved state, secretin level in circulation and secretin receptor level in epididymal adipose tissue were found to be upregulated. Using secretin receptor knockout (SCTR-/-) and secretin knockout (SCT-/-) mice as controls, it was found that secretin stimulated a dose- and time-dependent lipolysis in vitro and acute lipolysis in vivo. H-89, a protein kinase A (PKA) inhibitor, attenuated the lipolytic effects of secretin in vitro, while secretin induced an increase in cAMP dependent PKA activity in vivo. Using western blot analysis, secretin was found to phosphorylate hormone sensitive lipase (HSL) at serine residue 660. Additionally, immunofluorescent studies revealed that secretin stimulated translocation of HSL from cytosol to surface of lipid droplet subsequently leading to lipolysis. Under excess energy condition, when SCTR-/- mice and its littermates SCTR+/+ mice were subjected to high fat diet (HFD) feeding for 3 months, it was found that SCTR-/- mice gained lesser weight. Nuclear magnetic resonance imaging revealed that SCTR-/- mice exhibited lower body fat content. Additionally, HFD-associated hyperleptinaemia was alleviated in SCTR-/- mice along with metabolic syndrome as they performed better in insulin and glucose tolerance tests. Continuous monitoring by indirect calorimetry revealed similar food intake, energy expenditure and locomotor activity between SCTR-/- and SCTR+/+ mice. Interestingly, intestinal fatty acid absorption, measured by a noninvasive method, was impaired in HFD-fed SCTR-/- mice. While postprandial triglyceride release was reduced in SCTR-/- mice, it also had a significant reduction in transcript and protein levels of CD36 and its downstream mediator MTTP. Secretin, when incubated with isolated enterocytes, upregulated the expression of CD36. In summary, during starvation, secretin stimulates lipolysis through a HSL and PKA mediated pathway. When fed a HFD, SCTR-/- mice is resistant to diet induced obesity due to impaired intestinal lipid absorption. A novel short positive feedback pathway between CD36 and secretin, functioning to maximize lipid absorption, is also being proposed. Thus for the first time, two independent role of secretin in lipolysis and in intestinal lipid absorption were discovered along with their mechanistic insights. This study paves way for developing new therapeutic strategies against metabolic disorders associated with lipid metabolism. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Cyclopropenoid fatty acids (CPFA), which are a group of fatty acids produced by plants of the order Malvales, are known to induce adverse physiological effects when administered to a variety of animal species. A structurally strained cyclopropene ring is present in all CPFA and is believed responsible for the toxic action of these fatty acids. Dietary consumption of CPFA by mammals, poultry and fish has resulted in toxic responses including hepatic damage, impaired reproductive capabilities and sizeable alterations in lipid metabolism. Furthermore, CPFA have been identified as mildly carcinogenic and strongly cocarcinogenic towards rainbow trout (Salmo gairdneri). The mechanism by which CPFA enhance carcinogenesis is currently not understood. The research in this thesis has therefore been directed toward obtaining a better understanding as to how CPFA induce toxic responses in rainbow trout. Hepatic plasma membranes were isolated from both control trout and trout which had consumed dietary CPFA. The plasma membranes were then compared via the use of electron microscopy, chromatographic analysis of phospholipid and fatty acid content, two dimensional polyacrylamide gel electrophoresis of proteins, and Western blot analysis of concanavalin A sensitive glycoproteins. Electron micrographs revealed that control plasma membranes appeared more homogeneous than CPFA membranes and were characterized by more membrane sheets and less vesicularization. The analysis of enzyme activities revealed that CPFA caused a decrease in whole liver glucose-6-phosphatase activity and that control plasma membranes expressed slightly higher glucose-6-phosphatase and 5'-nucleotidase activities as compared to CPFA membranes. Although dietary CPFA appeared to have no effect on the phospholipid content of the plasma membranes, significant alterations in the fatty acid profiles of ethanolamine and choline phospholipids were observed. CPFA caused a decrease in palmitic, palmitoleic and oleic acids while the level of stearic and docosahexaenoic acids subsequently increased. Differences between the protein content of control and CPFA plasma membranes were made clear through the analysis of electrophoretic and Western blotting data. Membranes isolated from fish fed CPFA contained several proteins of high molecular weight (above 66,000 daltons) and other proteins of high isoelectric point that were not present in control plasma membranes. Additionally, two families of glycoproteins which had previously been identified as microsomal in origin were detected only in CPFA plasma membranes. A discussion concerning the possible causes and biological ramifications of the observed subcellular alterations caused by CPFA insult is also presented in this thesis. / Graduation date: 1989

Introduction: The relationship between pancreatitis and dyslipidaemia is unclear and has never been studied in a South African context. Patients and methods: A prospective evaluation of all admissions with acute pancreatitis to a regional hospital general surgical service was performed to ascertain its relationship to dyslipidaemia. Aetiology was determined by history and ultrasound assessment. Disease severity was assessed using a modified Imrie score and an organ failure score. Body mass index was calculated. A lipid profile was obtained. Abnormal profiles were repeated. Secondary causes of dyslipidaemia were noted. A comparison of the demographic profile, aetiology, disease severity scores, complications and deaths were made in relationship to the lipid profiles. Results: From June 2001 to May 2005, there were 230 admissions, of whom 31% were women and 69% men. The median age was 38 years(range 13- 73). The pancreatitis was associated with alcohol in 146(63%), gallstones in 42(19%) and idiopathic in 27(12%). The amylase was significantly higher with a gallstone aetiology (p / Thesis (MMedSc)-University of KwaZulu-Natal, 2006.

Abstract not available