Organismal Fructose Metabolism in Health and Non-Alcoholic Fatty Liver Disease.

Simple Summary The consumption of dietary fructose as sugar and high fructose corn syrup (HFCS), which is abundant in soft drinks, has markedly increased. This trend has been accompanied by an alarmingly increased incidence of non-alcoholic fatty liver disease (NAFLD). Recent studies using disease animal models such as mice and rats have revealed several important aspects of how our body handles fructose, especially when it is consumed in a large amount. Moreover, not only our bodily organs, but also microorganisms residing in the gut, have been shown to actively digest fructose and contribute to NAFLD. In this article, we summarize recent progress in our understanding of fructose metabolism at the organismal level. This review assembles scientific evidence that encourages the public to avoid an excess intake of fructose to prevent NAFLD and suggests potential drug targets to treat the disease. NAFLD has alarmingly increased, yet FDA-approved drugs are still lacking. An excessive intake of fructose, especially in liquid form, is a dietary risk factor of NAFLD. While fructose metabolism has been studied for decades, it is still controversial how fructose intake can cause NAFLD. It has long been believed that fructose metabolism solely happens in the liver and accordingly, numerous studies have investigated liver fructose metabolism using primary hepatocytes or liver cell lines in culture. While cultured cells are useful for studying detailed signaling pathways and metabolism in a cell-autonomous manner, it is equally important to understand fructose metabolism at the whole-body level in live organisms. In this regard, recent in vivo studies using genetically modified mice and stable isotope tracing have tremendously expanded our understanding of the complex interaction between fructose-catabolizing organs and gut microbiota. Here, we discuss how the aberrant distribution of fructose metabolism between organs and gut microbiota can contribute to NAFLD. We also address potential therapeutic interventions of fructose-elicited NAFLD.