Diabetic status modulates the effect of single nucleotide polymorphisms associated with NAFLD

Diabetic status modulates the effect of a SNP associated with NAFLD

Non-alcoholic steatohepatitis (NASH) is a common disease affecting approximately 1 billion people globally, so early identification of susceptible individuals is critical to accurate hepatology. In this issue, Takebe et al. Use of human liver organoids and collectively perform population-based phenotypic analysis under insulin-insensitive conditions to investigate key genetic drivers of NASH. In the image, many flying butterflies with liver-like wings indicate the presence of liver organelles on a “population” scale. Some butterflies are caught by the Nash spider’s web, which demonstrates a steatohepatitis-like phenotype. This is a metaphor that genetic association can be better captured at a particular metabolic state, enabling efficient assessment of genetic markers of common disorders such as NASH. Credit: Research Institute, TMDU

It is known that context affects many areas. And now, researchers from Japan have found that a patient’s health context — that is, what other conditions a patient has — can determine whether a particular genetic mutation is beneficial or harmful. Researchers from Tokyo Medical and Dental University (TMDU) and Cincinnati Children’s Hospital Medical Center (CCHMC) have revealed that a genetic mutation controversially linked to liver disease conferred different levels of risk depending on whether patients had diabetes.

Non-alcoholic fatty Liver disease (NAFLD) is the most common liver disease, and it can progress to nonalcoholic steatohepatitis (NASH) including fat buildup, damage, and inflammation in the liver. Known genetic variants explain only a fraction of the risk of NAFLD/NASH, and researchers disagree about the significance of some mutations.

“The association of the glucokinase regulatory protein (GCKR)-rs1260326 mutation with NAFLD is widely debated,” says first author Masaaki Kimura at CCHMC. “This mutation appears to protect patients from diabetes and Chronic kidney failureHowever, it is associated with an increased risk of non-alcoholic fatty liver disease and other diseases.

To better understand the role of GCKR-rs1260326 in NAFLD/NASH, cells were taken from 24 donors and grown into small liver-like organs, called organelles. Feeding them excess fatty acids led to fat buildup, inflammation, and Insulin resistanceFeatures seen in the livers of patients with nonalcoholic steatohepatitis. The associations between genetic variants and characteristics of liver organoids were then closely analyzed.

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

video abstract. attributed to him: cell (2022). DOI: 10.1016/j.cell.2022.09.031

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

Unexpectedly, analysis of real-world patient data showed that the level of hepatitis in NASH patients with diabetes varies based on the presence or absence of the mutation: Diabetics Those with two copies of the mutation had high levels of hepatitis, while diabetic patients without copies of the mutated gene showed lower levels of inflammation.

Furthermore, the researchers found that treating patients with metformin, a commonly used diabetes drug, was successful only when the patients carried unstimulated copies of the GCKR. However, combined treatment with the drugs nicotinamide riboside and nitozoxanide improved the function of liver organelles with two copies of the GCKR-rs1260326 mutation.

“This finding indicates a new treatment approach that could have a real impact on the lives of patients with diabetes mellitus who do not respond to standard medications,” says Kimura.

With NAFLD affecting nearly 1 billion people globally, early identification of patients who need different types of care may improve the prevention and treatment of non-alcoholic fatty liver disease. In addition, this study shows that studying organelles ‘in a dish’ and integrating this information with clinical data can provide insights into complex and common diseases.

The article was published in cell.

more information:
Masaaki Kimura et al., Organoid phenotyping collectively informs genetic susceptibility associated with NASH metabolism, cell (2022). DOI: 10.1016/j.cell.2022.09.031

Journal information:

Provided by Tokyo University of Medicine and Dentistry

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