Natural Antioxidants for Non-alcoholic Fatty Liver Disease

Molecular Targets and Clinical Perspectives

Federico Salomone; Justyna Godos; Shira Zelber-Sagi


Liver International. 2016;36(1):5-20. 

In This Article

Clinical Perspectives

Many epidemiological studies have demonstrated an association between the consumption of natural polyphenols within fruits and vegetables with a decreased risk of developing chronic disease.[9] However, although different experimental models suggest that polyphenols favourably impact liver damage (Table 1) through common molecular mechanisms (Fig. 2), intervention studies yielded conflicting results (Table 2). For example, although a large amount of preclinical data have suggested a putative therapeutic role of resveratrol, there is conflicting evidence on clinical effects of this compound in the setting of human NAFLD.[91,92] Importantly, it has to be taken into consideration that the study reporting on detrimental effects of resveratrol on NAFLD patients supplemented study subjects with 3000 mg resveratrol per day for 8 weeks,[91] while the study showing beneficial effects, supplemented with 500 mg per day for 12 weeks.[92] Therefore, it can be hypothesized that even compounds exerting antioxidant and anti-inflammatory effects may be harmful at high doses, especially for the liver, which is responsible for detoxification. In this regard, it has to be taken into account that daily dietary intake of polyphenols may range 1786–744 mg/day and 1626–584 mg/day for men and woman respectively.[105]

Figure 2.

Molecular effects of polyphenols on NAFLD. Overall, experimental data collected so far indicate that polyphenols exert the following activities: in the hepatocyte, inhibition of de novo lipogenesis and promotion of FA oxidation, stimulation of insulin and AMPK signalling; in the resident macrophage (Kuppfer cell), inhibition of inflammatory cytokines production and modification towards an anti-inflammatory phenotype; in hepatic stellate cells: inhibition of proliferation, decrease production of reactive oxygen species (ROS) and fibrogenic cytokines.

Apart from dose, a further issue is the varying bioavailability, which appears to depend in a variety of factors, such as chemical structure, intestinal transit time, colonic microflora and many others.[9] Thus, the 'pharmaceutical' design of polyphenolic compounds in order to allow adequate bioavailability remains a priority. Randomized controlled trials evaluating the safety and efficacy of popular compounds such as silymarin and resveratrol have been recently completed or are ongoing (Table 3). Well-designed controlled trials assessing histological outcomes are needed to establish the impact of polyphenols not only on steatosis and inflammation but most of all on fibrosis which is the more important determinant of clinical outcomes in NAFLD.[113] However, since the use of repeated liver biopsies may be not possible because of ethical and practical considerations, the use of non-invasive markers of liver damage may be a promising, safe and cost-effective alternative for the evaluation of clinical outcomes.[114]