The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids

Choolson Jang, Sheng Hui, Wenyun Lu, Alexis Cowan, Raphael Morscher, Gina Lee, Wei Liu, Gregory Tesz, Morris Birnbaum and Joshua Rabinowitz

Cell Metabolism 2018. 27: 351-361.

Abstract

Summary Excessive consumption of sweets is a risk factor for metabolic syndrome. A major chemical feature of sweets is fructose. Despite strong ties between fructose and disease, the metabolic fate of fructose in mammals remains incompletely understood. Here we use isotope tracing and mass spectrometry to track the fate of glucose and fructose carbons in vivo, finding that dietary fructose is cleared by the small intestine. Clearance requires the fructose-phosphorylating enzyme ketohexokinase. Low doses of fructose are ?90% cleared by the intestine, with only trace fructose but extensive fructose-derived glucose, lactate, and glycerate found in the portal blood. High doses of fructose (?1 g/kg) overwhelm intestinal fructose absorption and clearance, resulting in fructose reaching both the liver and colonic microbiota. Intestinal fructose clearance is augmented both by prior exposure to fructose and by feeding. We propose that the small intestine shields the liver from otherwise toxic fructose exposure.

Our Thoughts on This Paper

Fructose has been associated with the increased prevalence of obesity and non-alcoholic fatty liver disease. In the recent work by Jang et al. a stable isotope tracer approach was used to interrogate the flux and metabolism of fructose and glucose in mice. While some previous work had suggested fructose is primarily metabolized in the liver, this work shows that the primary site of metabolism is the intestine, but that this is saturable above 0.5 g/kg in mice, or they project about a 3 g fructose dose in humans. Below this limit, the majority of fructose is metabolized within the intestine with key end-products including glucose (~40%), lactate (~20%), and alanine (~10%). Interestingly, in contrast to hepatic gluconeogenesis, intestinal glucose production is enhanced in the fed state, suggesting that other foods can protect from fructose “escape” from the small intestine. This work suggests a reconsideration of both normal fructose metabolism, and its relationship to the pathogenesis of metabolic syndrome. In humans, clarifying the limit wherein fructose escapes the intestinal metabolism, and how that limit is modified by other components of a meal should answer some of these questions.

These comments are crossposted on the Faculty of 1000 at doi:10.3410/f.732607607.793543134.

Written by Dave Bridges on March 18, 2018.

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