Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic.... Show moreNon-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic. NAFLD comprises a wide spectrum of liver damage ranging fat accumulation (steatosis) to steatosis with inflammation (non-alcoholic steatohepatitis, NASH), which can further progress to fibrosis. In particular patients with NASH have increased risk to develop other metabolic complications, such as cardiovascular disease.NAFLD is a complex disease, in which the origin and molecular mechanisms controlling the progression of simple steatosis to NASH remain poorly understood. Nevertheless, it is thought that inflammation is a critical component of NAFLD progression. This inflammation may be triggered by metabolic surplus (excess of energy or nutrients) and is also referred to as “metabolic inflammation”. White adipose tissue (WAT) is assumed to be largely involved in the development of metabolic inflammation. The studies described in this thesis contributed to the understanding of the role of WAT in the development of NAFLD and provide insight into the molecular processes that cause metabolic inflammation. Show less
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
