Mito
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http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30729-5
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.
Study Limitations
There is substantial epidemiological and experimental evidence linking fructose consumption to metabolic disease, especially fatty liver. The link between fructose and metabolic disease, however, remains controversial (van Buul et al., 2014; Caliceti et al., 2017; Jegatheesan and De Bandt, 2017). Nothing in the present manuscript addresses whether fructose is more toxic than other sugars or carbohydrates.
We do, however, definitively determine the main site of dietary fructose clearance in mice: the small intestine. Because higher doses of fructose overwhelm the small intestine and spill over to the liver, it is tempting to speculate that fructose metabolism in the small intestine is safe (physiologic), whereas fructose metabolism in the liver drives metabolic disease (pathologic, at least for individuals with consistent access to abundant high-cal- orie foods). We do not, however, test this hypothesis. Indeed, it is possible that intestinal metabolism of fructose drives metabolic disease.
Another important limitation regards the dose response to fructose. In fasted mice, there is a shift toward greater hepatic fructose metabolism between 0.25 g/kg and 1 g/kg fructose gavage. We consider it likely that this basic trend is conserved across many mammals lower doses of fructose are cleared by the intestine and higher doses spill over to liver but our current data are limited to C57BL/6 mice. Moreover, even if the basic trend is conserved, the dose response may vary. Understanding the associated dose-response pattern in humans is of critical importance, but not addressed experimentally here.
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.
Study Limitations
There is substantial epidemiological and experimental evidence linking fructose consumption to metabolic disease, especially fatty liver. The link between fructose and metabolic disease, however, remains controversial (van Buul et al., 2014; Caliceti et al., 2017; Jegatheesan and De Bandt, 2017). Nothing in the present manuscript addresses whether fructose is more toxic than other sugars or carbohydrates.
We do, however, definitively determine the main site of dietary fructose clearance in mice: the small intestine. Because higher doses of fructose overwhelm the small intestine and spill over to the liver, it is tempting to speculate that fructose metabolism in the small intestine is safe (physiologic), whereas fructose metabolism in the liver drives metabolic disease (pathologic, at least for individuals with consistent access to abundant high-cal- orie foods). We do not, however, test this hypothesis. Indeed, it is possible that intestinal metabolism of fructose drives metabolic disease.
Another important limitation regards the dose response to fructose. In fasted mice, there is a shift toward greater hepatic fructose metabolism between 0.25 g/kg and 1 g/kg fructose gavage. We consider it likely that this basic trend is conserved across many mammals lower doses of fructose are cleared by the intestine and higher doses spill over to liver but our current data are limited to C57BL/6 mice. Moreover, even if the basic trend is conserved, the dose response may vary. Understanding the associated dose-response pattern in humans is of critical importance, but not addressed experimentally here.