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The efficacy of a drug to prevent the accumulation of fat in the liver – a condition that often accompanies obesity and can result in dangerous fatty liver disease – has been further explored by researchers at the University of Oklahoma. Their research, which highlights the complexity of metabolic diseases, is published in the organization’s peer-reviewed journal The Proceedings of the National Academy of Sciences (PNAS).
The publication builds on a previous discovery made by Tiangang Li, PhD, and a team of researchers at the OU Health Harold Hamm Diabetes Center: a drug developed to suppress cancerous tumors can improve insulin sensitivity and reduce blood glucose (sugar) levels. The drug, known as MLN4924, works by preventing the degradation of a specific protein needed for all cells to respond to insulin. Following the discovery, Li received a grant from the National Institutes of Health to continue his research.
In a recently published study, conducted on mice, his research team knocked out a gene called Cul 3 present in the liver. When Cul 3 is present in the body, the drug blocks it to prevent protein degradation. Eliminating the gene led to a complete understanding of what happens when mice become obese on a high-fat diet.
Their discovery was both anticipated and surprising. Without the gene, fat did not accumulate in the liver of mice eating a high-fat diet, even though they were obese. However, the lack of fat formation in the liver caused fat to enter the bloodstream and other tissues, such as muscle, where it should not be stored. As a result, muscle — the body’s largest organ — responded poorly to insulin, and the mice developed high blood sugar.
“By destroying the gene, we aggressively prevented fat accumulation in the liver, but it actually worsened insulin resistance in muscle, which tells us that fat metabolism in these organs is interconnected,” Li said.
“These findings suggest that in addition to reducing liver fat, a simultaneous reduction in obesity and improvement in insulin sensitivity are important for treating fatty liver disease. This is because these improvements outside the liver are critical for preventing fat that enters the liver from being deposited in other tissues.”
The research also shows why treating chronic diseases such as type 2 diabetes and fatty liver disease is never easy — improvements in one area can cause negative effects in another. Still, the study was extremely helpful in understanding the process by which fatty liver disease occurs and what medicine is doing in the context of that disease, said study co-author Jed Friedman, PhD, director of the OU Health Harold Hamm Diabetes Center and professor in the OU College of Medicine.
“We have some promising ideas for future studies targeting potential ways to reduce fat accumulation in the liver while also improving insulin sensitivity,” Friedman said. “The way we are repurposing the drug in this study is exciting because so much is already known about the drug and its safety. We believe it has a lot of potential.”
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