The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids - PubMed (original) (raw)

The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids

Cholsoon Jang et al. Cell Metab. 2018.

Abstract

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.

Keywords: flux; fructose; gut; isotope tracing; metabolic disease; metabolomics; microbiome; small intestine; sucrose; sugar.

Copyright © 2017 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Isotope Tracing Reveals Differential Formation of Circulating Metabolites from Oral Glucose versus Fructose

(A) Experimental scheme. Mice received an oral gavage of 1:1 glucose:fructose (one unlabeled and the other U-13C labeled, 0.5 g/kg each) and metabolite labeling was measured by LC-MS. Glc, glucose; Fruc, fructose. (B) Oral fructose does not circulate primarily as fructose. Data show blood concentrations of the administered labeled hexose (either U-13C-glucose or U-13C-fructose, with the other administered in unlabeled form) and associated area under the curve (AUC0–120 min) for the labeled hexose normalized such that glucose AUC = 100% (N = 4). (C) Oral fructose forms circulating glucose and organic acids. Heatmap shows the percentage of labeled carbon atoms in the indicated circulating metabolites from the administered U-13C-hexose (N = 4). (D and E) Graphs show corresponding blood concentrations of labeled glucose (D) and glycerate (E) and associated normalized AUC0–120 min. (F) Normalized labeled AUC0–120 min for other organic acids (N = 4). (G) Mice received sucrose (1 g/kg) instead of the 1:1 mixture of glucose:fructose, with either the glucose or the fructose moiety of sucrose labeled (N = 3). The fructose moiety of oral sucrose forms circulating glucose. (H) Mice received a 1:1 mixture of unlabeled glucose and partially labeled fructose (carbons 1, 2, 3 or 4, 5, 6 labeled). Circulating glycerate, and to a lesser extent several other organic acids, is preferentially formed from carbons 4, 5, 6 of fructose. Red line indicates equal labeling from carbons 1, 2, 3 versus 4, 5, 6 (N = 4 for 1, 2, 3 and N = 3 for 4, 5, 6). Data are means and error bars are ±SE. *p < 0.05 by a two-tailed unpaired Student’s t test. Labeled concentrations refer to the sum of all labeled forms, in which each form is weighted by fraction carbon atoms labeled. AUCs are calculated by the trapezoidal rule. See also Figure S1.

Figure 2

Figure 2. Dietary Fructose Is Metabolized by the Small Intestine

(A) Schematic of glucose and fructose metabolism. (B) Circulating fructose is metabolized in the small intestine, liver, kidney, and pancreas. Mice received a 1:1 mixture of unlabeled glucose and U-13C-fructose via a 2 hr continuous intravenous infusion (0.02 µmol/g/min each) and labeled F1P, the direct product of fructose phosphorylation, was measured in tissues (N = 5). (C) Oral fructose labels F1P in the small intestine. Mice received an oral gavage of 1:1 unlabeled glucose:U-13C-fructose (0.5 g/kg each), and labeled F1P was measured in tissues (N = 5). Bar graph to the right shows AUC0–45 min for tissue F1P. (D) Oral glucose labels G6P in muscle. Mice received an oral gavage of 1:1 U-13C-glucose:unlabeled fructose (0.5 g/kg each), and labeled G6P, the direct product of glucose phosphorylation, was measured in tissues (N = 4). Bar graph to the right shows AUC0–45 min for tissue G6P. Data are means and error bars are ±SE. F1,6BP, fructose 1,6-bisphosphate; 3-PG, 3-phosphoglycerate; GA, glyceraldehyde; Quad, quadriceps; TA, tibialis anterior; iWAT and gWAT, inguinal and gonadal white adipose tissue; BAT, brown adipose tissue. See also Figure S2.

Figure 3

Figure 3. Most Fructose Is Cleared in the Small Intestine

(A) Schematic of digestive system and location of portal vein. (B) Oral fructose is processed prior to entering the portal vein. Data show portal vein concentrations of the administered labeled hexose (either U-13C-glucose or U-13C-fructose, with the other administered in unlabeled form) and associated normalized portal vein AUC0–30 min (N = 4 for labeled glucose and N = 5 for labeled fructose). (C) Oral fructose forms portal vein glucose. Mice received a mixture of unlabeled glucose and U-13C-fructose and the concentration of labeled glucose and fructose in the portal vein was measured. (D) Intestinal gluconeogenesis from oral fructose scrambles the hexose carbon atoms. Labeling pattern of portal vein glucose in mice receiving 1:1 glucose:fructose with either the glucose or the fructose U-13C labeled. (E and F) In Khk knockout (KO) mice, oral labeled fructose appears in the portal vein as labeled fructose (E) and not labeled glucose (F). Bars indicate labeled portal vein AUC0–30 min of the indicated hexose, normalized to wild-type (WT) mice (N = 5). (G) Normalized AUC0–30 min for labeled F1P in jejunum and liver from WT and Khk KO mice (N = 5). Data are means and error bars are ±SE. See also Figure S3.

Figure 4

Figure 4. Quantitative Analysis of Intestinal Fructose Metabolism

(A) Illustration of small intestine and associated circulation and mathematical equation for quantitation of intestinal fructose metabolism based on systemic-portal vein labeled metabolite concentration differences. (B) Mice received a mixture of U-13C-glucose and unlabeled fructose and the concentration of labeled glucose in the portal vein and tail vein was measured (N = 3). (C–F) Mice received a mixture of unlabeled glucose and U-13C-fructose and the concentration of labeled glucose (C), lactate (D), alanine (E), and fructose (F) in the portal vein and tail vein was measured (N = 4). (G) Fate of fructose in the intestine. Stacked bars show the fraction of fructose arriving to the intestine that is converted into each of the indicated metabolic products. Data are means and error bars are ±SE.

Figure 5

Figure 5. Intestinal Fructose Metabolism Is Saturable, with Excess Fructose Cleared by the Liver and the Colonic Microbiome

(A) Intestinal conversion of fructose to glucose saturates at high fructose doses. Mice received increasing doses of a 1:1 mixture of unlabeled glucose and U-13C-fructose, and the portal vein blood AUC0–30 min for labeled glucose and labeled fructose was measured (N = 3–5). (B) Ratio of labeled oral fructose appearing in the portal vein as fructose versus glucose, derived from data in (A). Note that the y axis is in a log scale. (C) High-dose fructose increases F1P in the liver. Mice received increasing doses of a 1:1 mixture of unlabeled glucose and U-13C-fructose, and intestinal and liver AUC0–45 min for labeled F1P was measured (N = 4–6). (D) High doses of fructose overflow into the colon. Mice received increasing doses of a 1:1 mixture of unlabeled glucose and U-13C-fructose by oral gavage and feces were sampled after 60 min (N = 5). (E) The colonic microbiome converts labeled oral fructose into F6P, but not F1P; sampling as in (D) (N = 4). (F) The colonic microbiome further metabolizes oral fructose into TCA intermediates and essential amino acids. Mice received a high-dose oral gavage of 1:1 glucose:fructose (one unlabeled and the other U-13C-labeled, 2 g/kg each) and feces were sampled after 120 min (N = 3). TIC, total ion counts. Data are means and error bars are ±SE. See also Figure S4.

Figure 6

Figure 6. Intestinal Fructose Metabolism Is Enhanced by Previous Fructose Consumption and by Feeding

(A) Mice received a 1:1 mixture of glucose and fructose (2 g/kg each) by daily gavage, with the fructose U-13C labeled on the measurement day. Data show systemic venous blood concentrations of labeled glucose derived from the oral labeled fructose (N = 5). (B and C) Relative transcript levels of Glut5 (B) and G6pc (C) in liver and jejunum normalized such that liver from the saline-treated group = 1. Tissues were harvested 2 hr after oral gavage of saline or glucose + fructose (2 g/kg each) (N = 4). (D) Mice received fructose in their drinking water (15% w/v) for 1 week, followed by gavage of a 1:1 mixture of unlabeled glucose and U-13C-labeled fructose (2 g/kg each) on day 7. Fructose was then removed from the drinking water for 1 week and the 2 g/kg gavage repeated. Data show systemic venous blood concentrations of labeled glucose derived from the oral labeled fructose (N = 5). (E) Mice received increasing doses of a 1:1 mixture of unlabeled glucose and U-13C-fructose and the portal vein blood AUC0–30 min for labeled glucose was measured, after fasting for 6 hr or re-feeding for 2 hr (N = 3–5). (F) Ratio of labeled oral fructose appearing in the portal vein as fructose versus glucose. Note that the y axis is in a log scale. (G) Overflow of fructose into the feces. Feces were sampled 60 min after oral gavage (N = 4). Data are means and error bars are ±SE. See also Figures S5 and S6.

Figure 7

Figure 7. Illustration of the Roles of Intestine and Liver in Fructose Metabolism

(A) It is commonly assumed that the small intestine passively transports fructose to portal circulation and the liver is a major organ for fructose metabolism. (B) We show that low-dose dietary fructose is cleared by the small intestine, which converts it into glucose and organic acids. High fructose doses overwhelm the intestinal capacity for fructose metabolism and extra fructose spills over to the liver.

Comment in

Similar articles

Cited by

References

    1. Bismut H, Hers HG, Van Schaftingen E. Conversion of fructose to glucose in the rabbit small intestine. A reappraisal of the direct pathway. Eur. J. Biochem. 1993;213:721–726. - PubMed
    1. Bravo S, Lowndes J, Sinnett S, Yu Z, Rippe J. Consumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles. Appl. Physiol. Nutr. Metab. 2013;38:681–688. - PubMed
    1. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am. J. Clin. Nutr. 2004;79:537–543. - PubMed
    1. Caliceti C, Calabria D, Roda A, Cicero AFG. Fructose intake, serum uric acid, and cardiometabolic disorders: a critical review. Nutrients. 2017;9:E395. - PMC - PubMed
    1. Chong MF, Fielding BA, Frayn KN. Mechanisms for the acute effect of fructose on postprandial lipemia. Am. J. Clin. Nutr. 2007;85:1511–1520. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources