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The role of high-fructose and high-fat exposures in the pathogenesis and progression of non-alcoholic fatty liver disease
Williams, Jonathan M.
May 19, 2020
Biochemistry, Biophysics and Molecular Biology
Since first being described in 1980, non-alcoholic fatty liver disease (NAFLD) has become an increasingly prevalent chronic disease that is now present in approximately 30% of the world’s population. NAFLD consists of a spectrum of progressive metabolic states in the liver ranging from a benign "fatty liver” all the way to liver inflammation and cirrhosis. Factors including oxidative stress, lipid peroxidation, mitochondrial dysfunction, ER stress, and insulin resistance have all been implicated in the onset and progression of the disease. Nevertheless, the pathogenesis and the molecular mechanisms involved in its progression are still poorly understood. With the relatively recent rise of fructose consumption, the hepatic metabolism of fructose has been proposed as one potential pathway that can mediate many of the factors that contribute to the development of NAFLD. Here, we set out to explore molecular mechanisms of NAFLD pathogenesis and progression in response to high-fructose and high-fat diets. In order to gain a better understanding of an ordered time-course of molecular events that occur within the cell during this progression, we cultured a HepG2 cell line and treated these cells with fructose and palmitate, on their own and in combination. We followed this by measuring fat accumulation, reactive oxygen species production, and changes in protein expression. We found that exposure to high-fat and high-fructose conditions results in stimulated lipid droplet formation and the production of greater levels of mitochondrial ROS. With this, our results showed that fructose contributes to these events most significantly when combined with a high-fat exposure. Altogether, this suggests that fructose can have a synergistic effect in the development of NAFLD, and it can potentially be most harmful to the liver when exposed in combination with a high-fat diet.
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