Novel insights in intestinal and hepatic fructose metabolism: from mice to men

Abstract

Purpose of reviewThe rise in fructose consumption in parallel with the current epidemic of obesity and related cardiometabolic disease requires a better understanding of the pathophysiological pathways that are involved.Recent findingsAnimal studies have shown that fructose has various effects on the intestines that subsequently affect intrahepatic lipid accumulation and inflammation. Fructose adversely affects the gut microbiome – as a producer of endotoxins and intermediates of de novo lipogenesis – and intestinal barrier function. Furthermore, intestinal fructose metabolism shields fructose away from the liver. Finally, fructose 1-phosphate (F1-P) serves as a signal molecule that promotes intestinal cell survival and, consequently, intestinal absorption capacity. Intervention and epidemiological studies have convincingly shown that fructose, particularly derived from sugar-sweetened beverages, stimulates de novo lipogenesis and intrahepatic lipid accumulation in humans. Of interest, individuals with aldolase B deficiency, who accumulate F1-P, are characterized by a greater intrahepatic lipid content. First phase II clinical trials have recently shown that reduction of F1-P, by inhibition of ketohexokinase, reduces intrahepatic lipid content.SummaryExperimental evidence supports current measures to reduce fructose intake, for example by the implementation of a tax on sugar-sweetened beverages, and pharmacological inhibition of fructose metabolism to reduce the global burden of cardiometabolic disease.

Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design

“…This offers a novel therapeutic concept for the treatment of type 2 diabetes and obesity. Accordingly, KHK inhibitors that target both isoforms have been investigated in clinical trials (Futatsugi et al, 2020;Kazierad et al, 2021;Saxena et al, 2022;Koene & Schrauwen, 2022) and have been released as chemical probes to the scientific community (Heine et al, 2023); however, no KHK inhibitor has yet made it to the market.…”

Editorial: Nutrition and the gastrointestinal tract

“…Based on the available evidence, the intake of no specific amino acid can be strongly recommended to enhance anabolic potentials or the immune modulating effects of high protein diets.'' Evi Koene et al [7] present an excellent paper on the novel insights of intestinal and hepatic fructose metabolism. They describe data in mice and human experiments.…”

“…Evi Koene et al [7] present an excellent paper on the novel insights of intestinal and hepatic fructose metabolism. They describe data in mice and human experiments.…”