Sweating it out: How physical activity can combat high genetic risk for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) continues to be a leading cause of chronic liver disease worldwide of great public health interest.1 Because physical inactivity and sedentary behaviour contribute heavily to disease pathogenesis, lifestyle modification with increased physical activity is a key intervention against NAFLD.2, 3 However, physical inactivity and other environmental factors do not act in isolation; rather, there is a complex interaction between environmental factors and a genetic predisposition that we are beginning to understand.4 Genome-wide association studies have allowed for the creation of polygenic risk scores for hepatic fat content.5 However, physical activity as a tool to offset increased genetic risk for NAFLD remains relatively unexplored. A recent study by Schnurr et al.6 examined the effect of physical activity on the genetic risk conferred by a polygenic risk score using 68 loci for elevation in alanine aminotransferase (ALT) as a surrogate for NAFLD in 250 000 participants from the UK. The authors observed that increased physical activity modestly attenuated genetic predisposition to elevated ALT level. In recognition of this, the American College of Sports Medicine has identified the relationship between genetic predisposition and physical activity in individuals with NAFLD to be a key unmet research and clinical need.2 In a recent edition of Liver International, Ge et al.7 used the UK Biobank to further explore the relationship between behavioural activity pattern and genetic risk for NAFLD. In nearly 340 000 participants with mean age 57 years and mean body mass index 27.2 kg/m2 who were followed for a median of over 12 years, the authors used a previously validated NAFLD-specific polygenic risk score,5 which includes the PNPLA3, TM6SF2 and MBOAT7 genes, to categorize individuals into low, medium and high risk. Physical activity was quantified by the validated International Physical Activity Questionnaire8 and categorized as either low (<600 metabolic equivalent of task [MET]-min/week), medium (600 to <3000 MET-min/week) or high (≥3000 MET-min/week). Sedentary behaviour was also categorized as low (<3 h/day), medium (3–5 h/day) or high (≥5 h/day). The present study consisted of mostly individuals of European descent, which is important given the NAFLD risk allele burden differs across racial and ethnic groups.9 Validating several previous reports,10-12 the authors found both moderate-to-high amounts of total physical activity as well as sitting less than 3 h/day to decrease the risk of NAFLD. If both favourable behaviours were achieved, the risk of incident NAFLD was reduced by 29% when compared to individuals who did not complete either. Perhaps more importantly, these favourable behavioural patterns offset the effect of genetic factors on NAFLD risk. High amounts of physical activity decreased the risk of incident NAFLD across all categories of genetic risk: 48% for low, 36% intermediate and 9% in individuals with high genetic risk when compared to individuals with low total physical activity (Figure 1). A similar trend was observed for sedentary behaviour where low sedentary time was associated with a reduction in incident NAFLD by 58% in low, 49% intermediate and 27% in high genetic risk individuals when compared to individuals with high sedentary behaviour. Moreover, if individuals reached both healthy activities, the high-risk genetic group had the greatest reduction of 10-year absolute risk of incident NAFLD. The findings by Ge et al.7 further reinforce the importance of regular physical activity and avoiding sedentary behaviour, and their impact on genetic risk of disease. While the study is unable to determine whether high amounts of physical activity and/or low amounts of sedentary behaviour alter gene expression or epigenetic factors, it is plausible to consider this as an intriguing possibility. Regular physical activity and in particular exercise training, a subtype of physical activity that is structured, repetitive and undertaken with a goal in mind,13 may have a profound impact on gene expression by influencing epigenetic modifications such as DNA methylation, histone modification, microRNA expression and transcription factor activity. While the majority of the scientific literature is focused on the effect of exercise training in skeletal muscle,14 hepatic genetic and epigenetic response to exercise training has also been explored, demonstrating that exercise modulates gene expression in animal models of obesity.15-17 These findings highlight the importance of epigenetic mechanisms as an interface between lifestyle modifications and alterations in disease-specific phenotypic expressions. Another intriguing line of question, on the heels of this provocative study, would be to assess the impact of obtaining a baseline polygenic risk score before initiating a lifestyle intervention programme against NAFLD to determine whether knowledge about leading a healthy lifestyle can offset NAFLD risk, even in individuals with the greatest genetic predisposition. In other words, would the knowledge of the genetic susceptibility to NAFLD positively change human behaviour? It seems plausible that knowing one's specific genetic risk would reinforce individual motivation and seeking of a personalized approach.18 Knowing the greater genetic predisposition to NAFLD may allow for an individual to adopt healthier behaviours, including incorporating regular physical activity and decreasing sedentary behaviour, as a preventative approach in which an at-risk individual can be proactive rather than reactive in mitigating their increased risk. Moreover, understanding genetic risk could also improve adherence to exercise regimens which are abysmally low in individuals with NAFLD.19 Theoretically, if an individual knows they may require longer and more intense exercise sessions to overcome their genetic risk profile, this may allow them to better manage their expectations and to adhere and persist despite what may be slower progress when compared to an individual with lesser genetic risk. In perspective, knowing baseline genetic risk would allow for an individualized exercise prescription where genetic risk could be leveraged to optimize benefits and individuals may choose exercises and training modalities tailored to their genetic predisposition to maximize their effectiveness.20 And while neither the NAFLD polygenic risk score nor each individual at-risk gene included in the score has been shown to be impacted by different exercise prescriptions, several studies are underway investigating this important question.21 We are slowly leaving the current one-size-fits-all paradigm and progressing towards a future of precision medicine made of individualized treatment. In this process, the response to lifestyle changes based on genetic predisposition certainly seems something worth studying with the goal of better understanding who is going to derive measurable benefit from a particular programme. Whether race- and ethnic-based differences impact response to physical activity is also unknown in individuals who are at risk for NAFLD. Based on this study, a prediction would be that Hispanics would have less gain from exercise training than either non-Hispanic Caucasians or individuals of African ancestry given that Hispanics have the greatest NAFLD risk allele risk burden and individuals of African descent the lowest.9 We would also suggest this as another line of future investigation worth studying. In summary, leading a healthy lifestyle with high amounts of physical activity and low sedentary behaviour remains an important preventative and treatment strategy for patients with or who are at risk for NAFLD. While the role of routine testing for genetic risk prior to initiating lifestyle intervention remains unknown, especially regarding its impact on human behaviour, we look forward to future studies addressing this highly relevant question. Understanding how to best frame lifestyle recommendations is essential to improve adherence to lifestyle intervention programmes and, ultimately, clinical outcomes. National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K23DK131290 (Stine). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. JS—Research Funding from Astra Zeneca, Galectin, Noom Inc, Novo Nordisk and Zydus, Consulting for Novo Nordisk. Data sharing is not applicable to this article as no new data were created or analysed in this study.