New Drugs to Target Hypertriglyceridemia Inducing Protein

Diabetes researchers have found that by blocking the production of Forkhead Box O1 (FoxO1) protein in the liver they could lower levels of triglycerides in obese and diabetic animals.

Investigators at Children's Hospital of Pittsburgh (PA, USA) genetically engineered a line of mice to express an active FoxO1 transgene. These animals demonstrated increased FoxO1 activity that was associated with enhanced microsomal triglyceride transfer protein (MTP) expression, augmented very low-density lipoprotein (VLDL) production, and elevated plasma triglyceride levels. In contrast, RNAi-mediated silencing of liver FoxO1 was associated with reduced MTP and VLDL production in adult mice.

The investigators wrote in the June 2008 issue of the Journal of Clinical Investigation that both an abundance of FoxO1 in the liver and increased MTP production were found in mice with abnormal triglyceride metabolism. These findings suggested that FoxO1 mediated insulin regulation of MTP production, and that augmented MTP levels could be a causative factor for VLDL overproduction and hypertriglyceridemia in diabetes.

"Our latest findings suggest that we may eventually be able to develop drug therapies that inhibit FoxO1, which would thereby inhibit the production of proteins that lead to elevated triglyceride levels in people who are obese and/or who suffer from type 2 diabetes,” said senior author Dr. Henry Dong, PhD, a diabetes researcher at Children's Hospital of Pittsburgh. "Hypertriglyceridemia is a known risk factor for developing heart disease, the leading cause of death in the United States.”


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