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Novel liver organoid technology provides insights about fatty liver disease and type 2 diabetes

Researchers used novel technology to develop mini-livers, or organoids, to gain new understanding about how a genetic variant plays a context-dependent role in fatty liver disease with or without type 2 diabetes. Nonalcoholic fatty liver disease (NAFLD), in which excess fat builds up in the liver, can lead to liver inflammation and damage, and result in a more aggressive disease called non-alcoholic steatohepatitis (NASH). NASH can progress to scarring of the liver, liver cancer, and liver failure. Many people with NAFLD, however, do not develop NASH, suggesting additional factors, like certain genetic variants and the presence of conditions like type 2 diabetes, might influence susceptibility to severe liver disease. Identification of these factors and how they affect disease progression could inform personalized prevention and treatment strategies.

In new research, scientists used cutting-edge technology to grow liver organoids modeling NAFLD/NASH from induced pluripotent stem cells generated from 24 female and male donors. They used these organoids to examine genetic contributors to NAFLD/NASH, finding that a variant of the glucokinase regulatory protein (GCKR) gene was associated with fat accumulation. Other studies have implicated GCKR in NAFLD/NASH, although its role has been unclear. Building on this finding, the scientists examined clinical data from over 1,000 people with NASH—mostly middle-age White women with obesity. They were surprised to discover that the presence of the GCKR variant had differing effects on liver health. The presence of the GCKR variant was protective of liver function when a person’s hemoglobin A1c (HbA1c; a measure of average blood glucose [sugar]) level was in a non-diabetic range. In contrast, the variant’s presence was harmful when HbA1c levels were in a diabetic range. These observations suggest that HbA1c levels may be used to help predict the severity of liver disease progression in people with the GCKR variant—toward developing more personalized medicine approaches. To study the connection between NAFLD and diabetes further, they treated the NAFLD/NASH liver organoids with metformin—the first-line drug for people with type 2 diabetes—and found that metformin may exacerbate liver disease in the presence of the GCKR variant. However, treating the organoids with different drugs appeared to stabilize the organoids’ function, suggesting that people carrying the variant could benefit from alternate diabetes treatments to protect liver health.

These observations—made by integrating data from novel personalized liver organoid analyses with clinical data—give new understanding of how a genetic variant contributes to liver disease severity in people with and without type 2 diabetes. Such insights represent a significant step forward toward identifying people who are at higher risk of developing severe liver disease and informing personalized therapies to protect their liver health.

Kimura M, Iguchi T, Iwasawa K,…Takebe T. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 185: 4216-4232.e16, 2022.

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