How Diet and Genetics Shape Fatty Liver Disease Risk in Youth

Kyle Salmon, MSPH and Wei Perng, PhD, MPH

​Diet and health: truth in an old English idiom.
There’s an old English idiom that goes, “One man’s meat is another man’s poison.” It reminds us that what is healthy or enjoyable for one person might be unpleasant for another. This idea becomes relevant when it comes to changing our diets to mitigate the risk of chronic metabolic diseases. Nutrition isn’t one‑size‑fits‑all, and there are many other factors that shape how diet affects health. This is important when we look at a condition strongly shaped by diet, such as metabolic dysfunction-associated steatotic liver disease (MASLD).

MASLD, once known as non-alcoholic fatty liver disease (NAFLD), occurs when fat builds up in the liver. It is the most common chronic liver disease worldwide, affecting 2 in 5 adults. With the rise of the childhood obesity epidemic, MASLD prevalence has risen among children and adolescents, affecting approximately 10% of the pediatric population and up to 35% of youth with obesity. The primary strategy for preventing MASLD is lifestyle modifications, such as making healthful diet changes – e.g., reducing added sugar intake in foods and beverages, focusing on whole foods as opposed to process foods, and consuming healthy fats instead of trans and saturated fats. Yet lifestyle alone is not the only piece of the puzzle; genetic factors play a role as well.
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Our DNA helps explain why diet affects people differently.
When it comes to metabolic diseases like MASLD, one gene of particular interest is the PNPLA3 gene, which provides instructions for making an enzyme that regulates fat storage and the breakdown in liver and fat cells. For this reason, the PNPLA3 gene is strongly associated with the risk of obesity, type 2 diabetes, and MASLD. According to some studies, individuals who have the high-risk genotype of PNPLA3 are 88% more likely to develop MASLD than their lower-risk counterparts, highlighting the importance of identifying protective factors in this vulnerable subgroup.

To investigate potentially protective dietary habits and their interactions with PNPLA3 genotype, in a study with my colleagues, we used data from 381 adolescents in the Denver-based EPOCH cohort. Specifically, we characterized a dietary pattern that is inversely associated with liver fat and investigated whether this association varies by an individual’s level of genetic risk. We found that a dietary pattern composed of vegetables, fruit, nuts and seeds, oatmeal, sports bars, crackers and sandwiches, and beef was associated with lower liver fat, especially among youth with the high-risk allele for PNPLA3. While foods like veggies, fruits, nuts, and whole grains, align with protection against metabolic disease, other foods, such as sports bars, crackers, and sandwiches, were unexpected, as these are ultra-processed, refined, and typically linked to unfavorable health outcomes. We hypothesized that this dietary pattern captures an active, on-the-go lifestyle that may be especially beneficial for adolescents with elevated genetic risk for metabolic disease.

Is the “active, on-the-go” dietary the golden ticket to preventing MASLD?
Not exactly. Because our dietary habits and daily routines do not exist in isolation, the on-the-go dietary pattern may reflect a broader active lifestyle, which could be the real protective factor. Although our analysis accounted for physical activity levels, there may still be differences in activity that our data could not fully capture. We also note that these findings should not overshadow the importance of maintaining a balanced diet. Regularly consuming foods such as fruits and vegetables, whole grains, and nutritious snacks remains an important strategy for supporting overall health, including liver health. Ultimately, further research is needed to better understand how specific foods and nutrients within this dietary pattern contribute to MASLD risk, as well as the underlying biological mechanisms that may explain these associations and, accordingly, lend credence to our findings.
At the same time, this research delivers a hopeful message: even for individuals with a high genetic risk of MASLD, lifestyle changes may still make a meaningful difference. Encouraging dietary patterns that are both nutritious and realistic for adolescents could help pave the way for more personalized and effective strategies to prevent and manage MASLD and other leading metabolic diseases.

Author 
Wei Perng is an Associate Professor in the Department of Epidemiology at the Colorado School of Public Health. Her research revolves around perinatal origins of childhood obesity and related metabolic consequences. She has two boys and one dog, and enjoys napping (see former) in her free time. 
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Kyle Salmon is a Senior Data Analyst and Database Coordinator at the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus. She completed her MSPH in Human Nutrition at the Johns Hopkins Bloomberg School of Public Health. Her research interest includes chronic disease prevention from a nutrition lens, food security, and food as medicine. Kyle enjoys traveling, hiking, camping, skiing, and seeing live music.