The study, published in The Proceedings of the National Academy of Sciences (PNAS), explores the intricacies of metabolic illnesses by examining the effectiveness of a medication designed to prevent liver fat accumulation. This condition, which often coexists with obesity, can lead to severe fatty liver disease. Conducted by researchers at the University of Oklahoma, the study builds on earlier work by Tiangang Li, PhD, and his team at the OU Health Harold Hamm Diabetes Center. Their previous research identified that MLN4924, a drug initially developed to suppress cancerous tumors, also improves insulin sensitivity and lowers blood glucose levels by preventing the degradation of a specific protein crucial for cellular insulin response.
In the recent study involving mice, the researchers eliminated a gene in the liver called Cul 3. The absence of this gene allowed the team to better understand the effects of a high-fat diet on obese mice. Normally, the drug inhibits Cul 3 to prevent the degradation of the protein. The results of gene elimination were both expected and surprising. Despite the mice becoming obese, they did not accumulate fat in their livers when the Cul 3 gene was absent. However, this led to unintended consequences, as the lack of liver fat accumulation caused fat to enter the bloodstream and deposit in other tissues, such as muscle, where fat is not typically stored.
This redistribution of fat resulted in the muscle, the body’s largest organ, having a reduced response to insulin, leading to high blood sugar levels. The findings highlight the complexity of metabolic diseases, demonstrating that interventions targeting one aspect of metabolism can have unforeseen effects on other organs. Dr. Li’s ongoing research, supported by a grant from the National Institutes of Health, continues to investigate these complex mechanisms with the goal of developing more effective treatments for obesity-related conditions.
“By eliminating the gene, we aggressively prevented fat accumulation in the liver, but this actually worsened insulin resistance in the muscle, which tells us that fat metabolism in these organs is interconnected,” Li stated.
“These findings suggest that, in addition to lowering liver fat, the simultaneous reduction of obesity and improvement of insulin sensitivity are important for treating fatty liver disease. That’s because these improvements outside the liver are critical for preventing the fat that enters the liver from also building up in other tissues.”
The research underscores the complexity of treating chronic conditions like Type 2 diabetes and fatty liver disease, highlighting that improvements in one area can potentially trigger negative effects in another. Despite these challenges, the study has significantly enhanced our understanding of the mechanisms underlying fatty liver disease and the effects of treatment. According to study co-author Jed Friedman, Ph.D., director of OU Health Harold Hamm Diabetes Center and professor at the OU College of Medicine, the findings are invaluable for comprehending how fatty liver disease develops and how drugs interact with this condition.
“We have some promising ideas going forward to target potential pathways to lower liver fat accumulation while also improving insulin sensitivity,” Friedman stated. “Drug repurposing like we’re doing in this study is exciting because so much is already known about the drug and its safety. We believe it holds a lot of possibility.”
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