Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease worldwide. NAFLD can lead to loss of liver function and eventually progress to liver cancer. There is an urgent need for more knowledge about underlying disease-causing processes and for new treatment options, as there is no currently approved treatment. Therefore, one of the aims of this thesis was to better characterize metabolic dysfunction in the liver itself, but also in the gut and the adipose tissue that may be involved in NAFLD development. We also tested several nutritional interventions as potential new treatment strategies for NAFLD. To this end, various studies have been performed with Ldlr-/-.Leiden mice that develop NAFLD comparable to that of humans. In conclusion, we provided new insights into the dynamics of metabolic dysfunctions in multiple organs during NAFLD development. These insights underline the importance of a multi-organ approach in the development of new treatment strategies aiming to prevent or attenuate NAFLD. Specific metabolic dysfunctions were targeted with novel nutritional interventions including prebiotics, marine phospholipids and short-chain fatty acids. The results of these studies demonstrate that nutrients can be used to reduce chronic inflammation and oxidative stress, and restore metabolic homeostasis in multiple organs simultaneously.