Abstract
Simple SummaryThe 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.
Highlights
Technical breakthroughs in the food industry have impacted our diets in many ways over the last century
It is crucial to determine to what extent the findings in animal models reflect fructose metabolism in humans
Fructose feeding experiments in rodents have consistently indicated that a chronic intake of high-dose fructose causes hyperlipidemia, insulin resistance, and non-alcoholic fatty fatty liver liver disease (NAFLD)
Summary
Technical breakthroughs in the food industry have impacted our diets in many ways over the last century. Glut whole-body knockout mice survive without any defects under typical chow diets, but they show lethal phenotypes upon fructose feeding [2] This severe fructose intolerance is accompanied by a distended large intestine due to unabsorbed fructose and fluid retention. Kim et al proved that this transcriptional regulation by fructose is mediated by the transcription factor, carbohydrate-response element-binding protein (ChREBP), by generating intestine-specific ChREBP knockout mice [18] These mice displayed completely suppressed Glut, KHK, and other fructolytic and gluconeogenic enzyme expression, even after chronic fructose feeding. Unlike Glut 5 or ChREBP knockout mice, which likely die due to intestinal extension, the lethality and pathological phenotypes of aldolase B knockout mice were largely rescued by blocking KHK activity [22] This indicates that F1P buildup is the major cause of detrimental phenotypes. It is crucial to determine to what extent the findings in animal models reflect fructose metabolism in humans
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