Diabetic status alters the impact of a single nucleotide polymorphism associated with NAFLD

Context is known to influence many spheres. And now, Japanese researchers have discovered that a patient’s health background, that is, what other conditions a patient is suffering from, can determine whether a specific genetic mutation is helpful or harmful. Researchers from Tokyo Medical and Dental University (TMDU) and Cincinnati Children’s Hospital Medical Center (CCHMC) have revealed that a genetic mutation with a controversial link to liver disease confers different levels of risk depending on whether the patient is diabetic.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can progress to non-alcoholic steatohepatitis (NASH) involving fatty accumulation, damage and inflammation of the liver. Known genetic variants explain only a modest fraction of the risk of developing NAFLD/NASH, and researchers disagree on the importance of certain mutations.

“The association of glucokinase regulatory protein (GCKR)-rs1260326 mutation with NAFLD is widely debated,” says first author Masaki Kimura of CCHMC. “This mutation appears to protect patients against diabetes and chronic kidney disease, but is associated with an increased risk of NAFLD and other diseases.”

To better understand the role of GCKR-rs1260326 in NAFLD/NASH, cells were taken from 24 donors and grown into tiny liver-like organs called organoids. Giving them more fatty acids led to fat accumulation, inflammation and insulin resistance, features seen in the livers of NASH patients. The connections between the genetic variants and the organoid characteristics of the liver were then closely analyzed.

“The results were very clear,” says lead author Takanori Takebe. “We found that the NAFLD/NASH risk related to the GCKR-rs1260326 mutation in our organoid model was very high, although it is rarely considered clinically significant.”

Organoids with two copies of the GCKR-rs1260326 mutation absorbed fat from their environment much more efficiently than other organoids, which explains how this mutation could cause patients to develop fatty liver disease.

Unexpectedly, analysis of real patient data showed that the level of liver inflammation in NASH diabetic patients differed depending on the presence or absence of the mutation: diabetic patients with two copies of the mutation showed high levels of liver inflammation, while diabetic patients without copies of the mutated gene showed only low levels of inflammation.

Additionally, the researchers found that treating patients with metformin, a commonly used drug for diabetes, only worked when patients carried unmutated copies of GCKR. However, combination treatment with the drugs nicotinamide riboside and nitozoxanide improved liver organoid function with two copies of the GCKR-rs1260326 mutation.

“This finding suggests a new therapeutic approach that could have a real impact on the lives of patients with diabetes who carry the mutation and do not respond to standard medications,” Kimura says.

With NAFLD affecting nearly one billion people worldwide, early identification of patients who need different types of care can improve NASH prevention and treatment. Additionally, this study shows that studying organoids “in a dish” and combining this information with clinical data can provide rich insight into complex and common diseases.

The article was published in Cell.

Provided by Tokyo Medical and Dental University