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Softic Lab Research | Overview

Samir Softic, MD

The Softic lab focuses on investigating the effects of sugar (fructose and glucose) metabolism on both normal chow and high-fat diets, as a risk factor for development of obesity, insulin resistance and non-alcoholic fatty liver disease.

We found that mice fed a high-fat diet (HFD) supplemented with sugar-sweetened water develop obesity, and fatty liver disease, but only fructose-supplemented mice develop insulin resistance, whereas glucose-supplemented mice remain insulin sensitive, in spite of accumulating a similar amount of total fat in the liver. Furthermore, fructose and glucose supplementation induces accumulation of unique types of fats in the liver. Fructose supplementation promotes hepatic synthesis of free fatty acids, whereas glucose stimulates synthesis of inert triglycerides.

Fructose effects are dependent on ketohexokinase (KHK), an enzyme that catalyzes the first step of fructose metabolism in the liver. KHK was elevated in obese adolescents who had advanced fatty liver disease, as compared to weight-matched subjects that had normal amount of fat in their liver. Additionally, knockdown of KHK, in mice, resulted in decreased hepatic fat deposition and improved insulin signaling. These data suggest that inhibition of fructose metabolism could be a good therapeutic target for treatment of fatty liver disease and diabetes.

In our follow up experiments we are examining the effects of fructose and glucose supplementation on fatty acid oxidation and mitochondrial function.