Sugar Metabolism in Fatty Liver Disease

Increased intake of high-fat diet (HFD) and sugar sweetened beverages has contributed to the rise of obesity epidemic, which has devastating consequences on human health. As obesity affects ever increasing percent of our population, the life expectancy in the USA is expected to decrease for the first time in history. Much of the initial research on obesity has focused on the effects of HFD as a driver of poor metabolic outcomes. Over the last three decades we have learned that some fats, such as monounsaturated and polyunsaturated fatty acids found in olive oil, for example, actually promote health, while all-trans saturated fatty acids and cholesterol are particularly associated with poor health outcomes. As a product of this research, the intake of all-trans saturated fats has decreased on a population level, but unfortunately, this intervention did not translate to a decrease in obesity expansion or in poor health outcomes. More recently, the contribution of sugar to the development of obesity epidemic has experienced a renewed interest. As a result of largely descriptive epidemiologic data, a number of countries including UK, Mexico and several US cities have newly instituted a sugar tax, as means of curbing obesity epidemic. Furthermore, FDA for the first time now, mandates disclosure of sugar content on all food labels. Lastly, the majority of key drug companies are developing inhibitors of sugar metabolism as a treatment for obesity, fatty liver disease and insulin resistance. As an example, Pfizer has a KHK inhibitor in phase 2A clinical studies and our collaborator Alnylam Pharmaceuticals is also vigorously pursuing this target. In spite of renewed interest and policy changes across the globe, the mechanism by which sugar intake contributes to poor metabolic outcomes is largely unknown and whether some sugars could be more deleterious to health than the others. In order to tackle these important questions we supplemented mice with fructose- or glucose-sweetened water, both on normal chow or high-fat diets. We chose to compare fructose and glucose, as these monosaccharides are found in the most commonly consumed sweeteners, sucrose and high-fructose corn syrup. Furthermore, fructose and glucose have equal caloric density, excluding the possibility that the difference in their metabolic effects is secondary to increased caloric intake. We found that fructose supplemented mice on HFD developed obesity, fatty liver disease and insulin resistance, whereas glucose supplemented mice remained sensitive to the action of insulin, in spite of accumulating similar amount of fat in the liver. These divergent effects are in part mediated by different type of fat accumulation in the liver, as fructose promotes endogenous synthesis of free fatty acids, while glucose stimulates assembly of fatty acids into inert triglycerides. We also showed that human subjects with fatty liver disease have increased levels of ketohexokinase (KHK), the first enzyme of fructose metabolism and that liver-specific knockdown of KHK led to a decrease in liver lipid accumulation and improved insulin signaling in mice. In this application we propose to dissect the metabolic pathways that are affected by sugar metabolism. We will investigate the effects of fructose and glucose supplementation on fatty acid synthesis and fatty acid oxidation pathways, two major drivers to liver lipid accumulation. We will also study insulin signaling pathway, as insulin promotes fat synthesis and decreases fat utilization. Lastly, using new state of the art proteomic analysis we will identify novel pathways that are affected by fructose or glucose supplementation and by KHK knockdown. In the second aim, we will study the effects of sugar on mitochondria, as these organelles regulate energy homeostasis in the cell. We will determine whether fructose-induced mitochondrial fragmentation is mediated through KHK. We will also determine the effects of sugars on ER stress, the pathway that can lead to mitochondria fragmentation and the effects of sugar on clearance of damaged mitochondria (mitophagy). Lastly we will study how sugar intake may modify post translational modification of mitochondrial proteins and thus affect global metabolism. The studies proposed in this application will discover new pathways that are affected by sugar metabolism and increase our molecular understanding of how specific sugars contribute to development of obesity and its complications. This research will also uncover and test new therapeutic targets that could abrogate poor outcomes associated with harmful sugar metabolism. Lastly we will provide valuable insights whether some sugar monosaccharides may be less harmful to health than the others.