Overload of nutrients can lead to diet-induced inflammation, also called metabolic inflammation, which is thought to play an important role in many metabolic diseases, including the development of... Show moreOverload of nutrients can lead to diet-induced inflammation, also called metabolic inflammation, which is thought to play an important role in many metabolic diseases, including the development of nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of pathologies that range from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis. The pathogenesis of NAFLD, including the sequence of events in time and the underlying mechanisms that initiate the transition from a fatty liver to NASH and fibrosis, remain poorly understood. Effective and reliable therapeutic approaches that are based on the understanding of the pathogenesis of NASH are therefore still lacking. In order to gain more insight into the mechanisms of NASH pathogenesis, we started with comparison of human NASH and experimental NASH. Subsequently, we provided evidence that activation of AP-1 and associated neutrophil infiltration is important for NAFL progression towards NASH and this can be induced experimentally by __metabolic__ dietary triggers of inflammation.Furthermore, we explored novel nutritional and pharmacological agents as potential strategies to combat NASH. Finally, we investigated the effects of high fat diet-induced metabolic overload on the liver in relation to inflammation in white adipose tissue and kidney, and the dysfunction of these tissues. Show less
In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between... Show moreIn this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism underlying this association remains unclear. Recently, attention has focused on the role of excessive accumulation of triglycerides (TG) in the liver (hepatic steatosis) in this association. Hepatic steatosis was considered a benign condition until it was discovered that a nonalcoholic fatty liver is associated with many cardiovascular risk factors. Subsequently, many studies have shown a strong association between hepatic TG content and hepatic insulin resistance. The studies in this thesis show that hepatic steatosis is actively and passively involved in the metabolic disturbances in the glucose and lipid metabolism. The prevalence of hepatic steatosis in western countries is high and will certainly increase with the epidemics of obesity and diabetes. This will put an increasing number of subjects at risk for disturbances in the glucose and lipid metabolism and concomitantly for cardiovascular disease. Show less
