Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. This review covers the influence of macronutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimated potential to induce improvement and/or even remission of NAFLD. Nonalcoholic Fatty Liver Disease: The ChallengeThe global burden of nonalcoholic fatty liver disease (NAFLD) (see Glossary), which ranges from steatosis to nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma, is rapidly rising [1]. Recent data reveal a world-wide prevalence of 24% among the adult population [2]. The etiology is multifactorial and yet incompletely understood, but involves accumulation of intrahepatic lipids (IHL), alterations of energy metabolism, insulin resistance, and inflammatory processes [3]. Besides genetic predisposition, unhealthy dietary habits and low levels of physical activity and regular exercising are the main modifiable risk factors for NAFLD. In the absence of approved pharmacological agents for the treatment of NAFLD, the current European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) Clinical Practice Guidelines for the management of NAFLD recommend lifestyle modification as the strategy of choice for preventing and improving NALFD [1]. They suggest to induce an energy deficit of 500-1000 kcal, leading to an associated weight loss of 7-10% by low-to-moderate fat, low-carbohydrate ketogenic or high-protein diets, and moderate-intensity aerobic exercise training with additional resistance training [1]. However, while there is clear evidence that weight loss improves IHL, only few people achieve the required 10% minimum weight loss required for clinically meaningful improvement or resolution of NASH and fibrosis [4]. Here, we discuss the recent evidence supporting or challenging this view.Is Nutritional Quality or Quantity More Important to Reduce IHL? Effect of Body Weight ReductionA surplus of 1000 kcal for 12 weeks in obese people, leading to a weight gain of 6% body weight, increases IHL by $50%, mainly through increased de novo lipogenesis together with reduced intrahepatic fatty acid oxidation [5], while fatty acid availability is less relevant in this setting [6,7]. Moreover, a single oral saturated fat load increases IHL, reduces hepatic insulin sensitivity in ...