[Truncated abstract] Iron and lipid metabolism are connected albeit the relationship involved is poorly understood. Variations in iron stores lead to inappropriate lipogenesis and processing of lipoproteins by hepatocytes. Conversely, dietary fat affects iron status. Hepatic damage has been demonstrated when iron and lipid deposition increases. It has been proposed that iron overload by generating oxidative stress causes lipid peroxidation and this is involved in the generation/progression of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). On the other hand NASH is also associated with increased hepatic iron loading and altered iron metabolism. It was the original intention of this research to study the derangement of iron metabolism in the background of NAFLD/NASH using the rat Lieber model, and to see whether there is progression of NAFLD/NASH with iron loading. The Lieber model was expected to develop NASH, however the rats developed a less progressed condition and remained within a range of NAFLD type I-II. Chapter 3 reports that although there was steatosis there was no inflammatory cell infiltrate and no increase in mRNA expression of proinflammatory cytokines, markers of oxidative stress and endoplasmic reticulum (ER) stress. These differences probably represent variation in the genetic background of the rats and/or other environmental factors. Failure to develop NASH in these rats necessitated a change in direction of the thesis and the data were then assessed from the perspective of the effects that lipids have on hepatic iron metabolic pathways and vice versa. Experiments were conducted to assess different dietary fat loads in combination with variations in iron treatment on lipid and iron metabolism, ranging from iron deficiency to iron loading. Chapter 5 shows that consuming a standard diet (35% fat) increased plasma lipids according to the level of iron present. Hepatic triglycerides (TG) were decreased with iron deficiency. Iron dextran injections loaded predominantly macrophages and produced occasional foci of lipid droplets with no inflammatory cell infiltrates. The mRNA expression of oxidative stress responsive genes, proinflammatory cytokines, ER stress genes, lipogenic regulatory/effector genes were not affected and there was no sign of apoptosis, indicating that iron loading from normal in combination with a 35% fat containing diet did not develop NAFLD. In Chapter 6 the same iron loading used in Chapter 5 was given with the high fat diet (71% fat) shown in Chapter 3 to produce NAFLD type II. Within this range of fatty liver, iron loading mainly of macrophages did not exacerbate the extent of NAFLD. Iron deficiency in combination with a high fat diet reduced hepatic lipid deposition, increased lipogenic gene expression and increased serum TG, suggesting that iron deficiency increased secretion and decreased peripheral clearance of lipoproteins. Chapter 7 compared the standard and high fat diets with variations in iron loading to gain insight into the mechanisms involved in the development of NAFLD type II. ER stress genes were increased in high fat groups suggesting it to be an important player for the generation of NAFLD...
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2009|