Non-alcoholic fatty liver disease (NAFLD) has become a major global health burden, leading to increased risk for cirrhosis, hepatocellular carcinoma, type-2 diabetes and cardiovascular disease. Lifestyle intervention aiming at weight reduction is the most established treatment. However, changing the dietary composition even without weight loss can also reduce steatosis and improve metabolic alterations as insulin resistance and lipid profile. The Mediterranean diet (MD) pattern has been proposed as appropriate for this goal, and was recommended as the diet of choice for the treatment of NAFLD by the EASL-EASD-EASO Clinical Practice Guidelines. The MD has an established superiority in long term weight reduction over low fat diet, but it improves metabolic status and steatosis even without it.However, the effect on liver inflammation and fibrosis was tested only in few observational studies with positive results. Furthermore, considering the strong association between NAFLD and diabetes and CVD, the MD has a highly established advantage in prevention of these diseases, demonstrated in randomized clinical trials. The individual components of the MD such as olive oil, fish, nuts, whole grains, fruits, and vegetables, have been shown to beneficially effect or negatively correlate with NAFLD, while consumption of components that characterize a Western dietary pattern as soft drinks, fructose, meat and saturated fatty acids have been shown to have detrimental association with NAFLD. In this review we will cover the epidemiological evidence and the plausible molecular mechanisms by which the MD as a whole and each of its components can be of benefit in NAFLD.

Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long-term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications.Keywords fibrosis -NASH -nutraceuticals -oxidative stress -polyphenols Abbreviations ACC, acetyl coenzyme A carboxylase; ACN, anthocyanins; AKT, serine-threonine protein kinase; AMPK, adenosine monophosphate-activated protein kinase; CD36, cluster of differentiation 36; CHREBP, carbohydrate-responsive element-binding protein; COX-2, cyclooxygenase 2; CYP2E1, cytochrome P450 2E1; CYP4A1, cytochrome P450 4A1; DJ-1, protein deglycase-1; EC-SOD, extracellular superoxide dismutase; EGCG, epigallocatechin gallate; ERK, extracellular receptor kinase; FA, fatty acid; FAS, fatty acid synthase; FFA, free fatty acid; GGT, gamma glutamyl transferase; GRP-78, 78 kDa glucose-regulated protein; GSH, glutathione; HDL, high density lipoprotein; HFD, high fat diet; HMG-CoA, 3-Hydroxy-3-Methyl-Glutaryl-CoA; HSC, hepatic stellate cell; ICAM-1, intercellular cell adhesion molecule type 1; IRS-1, insulin receptor substrate-1; JNK, Jun Nterminal kinase; LDL, low density lipoprotein; MCP-1, monocyte chemoattractant protein-1; NAD, nicotinamide adenine dinucleotide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NFkB, nuclear factor kappa B; NRF2, nuclear respiratory factor 2; PDGF-BB, platelet-derived growth factor-BB; PGC-1a, proliferator-activated receptor-gamma coactivator-1alpha; PI3K, phosphoinositide 3-kinase; PPAR-a, peroxisome pro...

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Authors contributions: CR provided data collection, statistical analysis, interpreted data and drafted the manuscript, KK, RY, SE, MM and MS provided the acquisition of data, interpreted data and critically reviewed the manuscript, CB, MG and FS provided the acquisition of data, HJM, MLA, HV, AG and JG interpreted data and critically reviewed the manuscript, EB and HG led the development of the study concept and design, interpreted data, drafted and finalized the manuscript.

Nonalcoholic fatty liver disease (NAFLD) is emerging as a major public health problem because of its association with increased cardiovascular and liver-related morbidity and mortality. Both genetic factors and lifestyle contribute to the pathogenesis of NAFLD. Lifestyle, including dietary habits and physical activity, is a modifiable risk factor and thus represents the main target for the prevention and treatment of NAFLD. In this review, we summarize the evidence regarding nutritional aspects (i.e. total energy intake, saturated fat and carbohydrates intake, certain foods or drinks and dietary patterns as a whole) in the treatment of NAFLD. In addition, we analyze the evidence concerning the independent effect of physical activity, including aerobic and resistance training, in the treatment of NAFLD. A therapeutic algorithm according to results from intervention trials is also provided for clinicians and other healthcare professionals involved in the management of NAFLD.