Summary
The impairment of liver function seen in non-alcoholic fatty liver disease, the main type of liver disease worldwide, has a multitude of harmful effects. When allowed to run its course, non-alcoholic fatty liver disease can cause end-stage liver disease and liver cancer. Excessive generation of fat by the liver is thought to underlie this disease. Omega-3 fatty acids such as DHA have been shown to counter excessive novel generation of fat by the liver.
 
Introduction
The liver is the largest internal organ of the body, pivotal for many physiological processes such as metabolism of macronutrients and medicine, maintaining lipid and cholesterol balance, blood volume regulation and proper immune system functioning. Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction–associated steatotic liver disease, is characterized by excessive accumulation of fat in the liver (>5% total liver weight) that is not caused by alcohol abuse. Currently, it is the leading type of liver disease worldwide. Two forms of NAFLD exist: (1) steatosis with no or mild inflammation, where liver cells have elevated fat levels. This can develop in (2) steatohepatitis, characterized by inflammation and injury of liver cells. Elevated liver cell fat production is suggested to underlie insulin resistance (driving type 2 diabetes) and NAFLD (Green et al., 2020). Correspondingly, these conditions are often comorbidities. Ultimately, NAFD can cause end-stage liver disease (chronic liver failure) and liver cancer. Currently, no approved medicinal treatment for NAFLD exists. The last decade has seen a steady increase in studies on the role of omega-3 fatty acids in liver disease, with many publications reporting a positive health effect.
 
Research findings
Aiming to investigate the effect of omega-3 fatty acids on new fat generation by the liver in non-diabetic men with a healthy or overweight BMI, Green and colleagues employed EPA+DHA supplementation (Green et al., 2020). Fifty-seven men (not suffering from NAFLD) aged 33 to 55 were divided in the supplementation group (24 men, 1.84g EPA + 1.52g DHA/day) or placebo group (23 men, 4g olive oil/day) and treated for 8 weeks. A mixed meal (containing fats and carbohydrates) was given to participants at the begin and end of the study to assess how the body processes the carbohydrates and fats in this meal. Before supplementation, all groups showed that the body uses carbohydrates of this meal for energy and stores fat. At the 8 week point, only the omega-3 supplementation group showed an increase in utilization of fat and a decrease of carbohydrates from the mixed meal to generate energy. Corresponding with this, the authors reported that the supplementation group showed a decrease in novel generation of fat by the liver whereas the placebo group displayed no differences.
 
Nobili and colleagues researched the effects of DHA supplementation on liver steatosis and insulin sensitivity in children with NAFLD (Nobili et al., 2011). Sixty overweight or moderately obese children with NAFLD a median age of 11-13 were equally divided into three groups, receiving either 97.5mg  algae-derived DHA, 195mg algae-derived DHA or a placebo (290 mg linoleic acid) daily for a period of 6 months. Blood samples were taken throughout the study to assess, amongst others, levels of DHA and insulin. Proving that supplementation-derived DHA was taken up by the body, the authors reported that serum DHA levels were higher in the DHA supplementation groups than the placebo group. By method of ultrasonography, the authors were able to detect that the liver fat content was reduced in DHA supplementation groups but was unchanged in the placebo group. Furthermore, insulin sensitivity increased in the DHA groups, together with a decrease of plasma fatty acid levels. As insulin activity stimulates production of energy through fatty acid metabolization, these findings correspond well. Insulin is a hormone that circulates in the blood and plays a central role in glucose and fat metabolism; the liver is a major target of insulin. Individuals with type 2 diabetes have a decreased sensitivity to insulin, which couples with their disturbed fat and glucose metabolism and contributes to obesity. The increased insulin sensitivity as a result of DHA supplementation in these groups might therefore be beneficial in light of obesity.
 
In a similar setup to the study by Nobili et al. (2011), Pacifico and collaborators examined the effects of DHA supplementation in 51 overweight or obese children suffering from NAFLD (Pacifico et al., 2015). For a period of 6 months, the DHA supplementation group of 25 children received 97.5mg algae-derived DHA and the placebo group of 26 children received 290mg linoleic acid per day. In agreement with the findings of Nobili et al. (2011), DHA supplementation caused a decrease in liver fat and visceral fat in children suffering from NALFD.
 
Conclusion
Supplementation with EPA+DHA in healthy male adults primes the body to increase the metabolization of fat after a mixed meal, leading to a decrease in novel fat generation by the liver. In the context of NAFLD, supplementation with DHA has been shown to reduce the pathological liver fat content in overweight and obese children. Nobili et al. and Pacifico et al. also reported an increase of insulin sensitivity in children suffering from NAFLD upon DHA treatment. Insulin resistance is a common comorbidity of NAFLD and a risk factor for cardiovascular disease; elevated liver cell fat production is suggested to lie at the heart of this resistance. This suggests that by reducing generation of fat by liver cells, DHA targets a shared mechanism of insulin resistance and NAFLD.
 
References
Green, C. J., Pramfalk, C., Charlton, C. A., Gunn, P. J., Cornfield, T., Pavlides, M., Karpe, F., & Hodson, L. (2020). Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism. BMJ Open Diabetes Research & Care, 8(1), e000871. https://doi.org/10.1136/bmjdrc-2019-000871
 
Nobili, V., Bedogni, G., Alisi, A., Pietrobattista, A., Risé, P., Galli, C., & Agostoni, C. (2011). Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: Double-blind randomised controlled clinical trial. Archives of Disease in Childhood, 96(4), 350–353. https://doi.org/10.1136/adc.2010.192401
 
Pacifico, L., Bonci, E., Di Martino, M., Versacci, P., Andreoli, G., Silvestri, L. M., & Chiesa, C. (2015). A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. Nutrition, Metabolism and Cardiovascular Diseases, 25(8), 734–741. https://doi.org/10.1016/j.numecd.2015.04.003