Is Liver Fat Written Into My Genes?

Genes control how we handle fat and where we put it

Fatty liver disease, or MASLD (metabolic dysfunction-associated steatotic liver disease), is becoming more common in children and teens. About one in six youth have it, and that number jumps to one in three children and teens who live in bigger bodies.

If you live in a bigger body, it can be helpful to understand how your genes might affect your liver. Some people are more likely to store fat in their liver because of tiny differences in their DNA. These small differences, called variants, are what make each of us unique, but certain variants in the genes that control fat can also mean we are more vulnerable than other people to fatty liver. While having these variants doesn’t guarantee liver fat, it can raise our personal risk, especially if we have higher body weight or insulin resistance.

Over 1,000 children and teens with higher body weight took part in many studies to understand which gene variants are linked to fatty liver. They did genetic testing, a glucose tolerance test to check for diabetes, fasting blood tests for fat measurements, and an MRI to measure liver fat. Some volunteers even had a liver biopsy.

Researchers found several gene variants that raised the risk of storing fat in the liver.

Let’s take a closer look at the two most common of these gene variants among teens with bigger bodies from our communities in Connecticut.

1. GCKR rs1260326 variant tells the liver to break down sugar and make more fat

First, researchers found that teens with the GCKR rs1260326 variant have more liver fat and more fat molecules (called triglycerides) in their blood than teens without the variant. In our population of kids, the variant was present in about 45% Caucasian kids, 36% Hispanic kids, and 13% African American kids.

This finding made sense because the liver can break down sugar (glucose) to make new fat (triglyceride). It does this using an enzyme called glucokinase. Glucokinase Regulatory Protein controls glucokinase. So, the next step was to understand what was different about the teens with the rs1260326 variant in their gene for Glucokinase Regulatory Protein (GCKR).

A small group of teens—half had the GCKR rs1260326 variant and half did not—did extra testing to measure how much fat their livers made before and after a sugary drink. The teens with the variant were already making more new fat from glucose, even before the sugary drink!

Overall, their livers made more fat than teens without the variant, which likely increases the chance that these fats stay in the liver. Fat also traveled out to the bloodstream, increasing the blood triglyceride levels. Doctors recognize fatty liver and high triglyceride levels in the blood as known risk factors for heart disease.

2.PNPLA3 rs738409 variant makes it harder for the liver to let go of fat

The PNPLA3 (patatin-like phospholipase domain-containing3) rs738409 variant is the most common of all the known variants associated with fatty liver. In the population who participated in these studies, the variant is present in about 42% Hispanic kids, 27% Caucasian kids, and 17% African American kids.

Researchers found that the kids with the PNPLA3 variant had more fat in their liver than kids without the variant. Having this gene variant didn’t make kids more or less fat overall, and it didn’t change their blood fat levels much.

Instead, having the variant means that their livers have a harder time breaking down certain fats to be released into the bloodstream, so the fat remains in the liver and accumulates over time.

Double Trouble: Both Genes Together

Importantly, when kids had both the GCKR and PNPLA3 variants, liver fat levels were even higher. The effect of each gene built upon one another, showing how genes can interact and affect health in complex ways.

Why Should I Care About My Genes?

First, when we know why something is happening, we can better prevent it.

For example, for people with the PNPLA3 variant, researchers found that choosing foods with certain types of fat matters. In one study, over 125 teens with bigger bodies carefully recorded their food intake for three days, and dieticians calculated the amount of omega-6 fatty acid and omega-3 fatty acid that were in their food.

For teens without the PNPLA3 variant, it did not really matter how much omega-6 fat or omega-3 fat they ate. However, teens with the variant who ate far more omega-6 fat than omega-3 fat had higher liver fat and greater liver damage. The teens with the variant who ate more of a balanced diet with omega-3 fat did better.

This is important because people with the PNPLA3 variant can decrease their liver fat by choosing specific foods and limiting others. Foods rich in omega-3 are salmon, tuna, and flaxseed oil, whereas foods rich in omega-6 are beef, pork, corn oil, and eggs. Research shows the healthiest balance between omega-3 and omega-6 intake is one omega-3 for every four omega-6.

Second, genetic screening for fatty liver variants (like PNPLA3, GCKR) in teens with bigger bodies can be more accurate than just looking at body size.

Ultimately, the goal is to personalize a plan for monitoring and offer effective options for prevention and treatment.

This report was written by Abigail Kelley and Clare Flannery, MD

Scientific Studies:

Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S. Hepatology. 2012 Mar;55(3):781-9. doi: 10.1002/hep.24806. Epub 2011 Dec 18. PMID: 22105854 Free PMC article.

Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. Santoro N, Caprio S, Pierpont B, Van Name M, Savoye M, Parks EJ. J Clin Endocrinol Metab. 2015 Aug;100(8):E1125-32. doi: 10.1210/jc.2015-1587. Epub 2015 Jun 4. PMID: 26043229 Free PMC article. Clinical Trial.

Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Goffredo M, Caprio S, Feldstein AE, D'Adamo E, Shaw MM, Pierpont B, Savoye M, Zhao H, Bale AE, Santoro N. Hepatology. 2016 Jan;63(1):117-25. doi: 10.1002/hep.28283. Epub 2015 Nov 16. PMID: 26457389 Free PMC article.

The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity. Cropano C, Santoro N, Groop L, Dalla Man C, Cobelli C, Galderisi A, Kursawe R, Pierpont B, Goffredo M, Caprio S. Diabetes Care. 2017 Aug;40(8):1082-1089. doi: 10.2337/dc17-0290. Epub 2017 Jun 13. PMID: 28611053 Free PMC article.

The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth. Umano GR, Caprio S, Di Sessa A, Chalasani N, Dykas DJ, Pierpont B, Bale AE, Santoro N. Am J Gastroenterol. 2018 Mar;113(3):376-383. doi: 10.1038/ajg.2018.1. Epub 2018 Feb 27. PMID: 29485130

A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Calí AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S. Hepatology. 2010 Oct;52(4):1281-90. doi: 10.1002/hep.23832. PMID: 20803499 Free PMC article.

Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, Caprio S. PLoS One. 2012;7(5):e37827. doi: 10.1371/journal.pone.0037827. Epub 2012 May 21. PMID: 22629460 Free PMC article.