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FATTY LIVER

Conversion of a dietary fructose: new clues from the gut microbiome

Nature Metabolism volume 2, pages 217–218 (2020)Cite this article

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Fructose, a monosaccharide derived from fruits, is primarily consumed in a form combined with glucose as sugar or as a component of high-fructose corn syrup added as a sweetener to processed foods and carbonated beverages. Increased consumption of fructose has emerged as a major contributor to non-alcoholic fatty liver disease, dyslipidaemia, insulin resistance and diabetes. Now Zhao et al. show that hepatic lipid synthesis is increased by fructose metabolism in both the liver and intestine.

The study by Zhao et al.4 challenges current knowledge and reveals a novel pathway of lipogenesis activation by fructose (Fig. 1). Using elegant in vivo isotope-tracer approaches (13C labelling) in mice with liver-specific ACLY deficiency, Zhao et al. show that fructose-derived carbons can be used for lipogenesis even in the absence of hepatic ACLY. These data are supported by compelling evidence that dietary fructose is converted by the gut microbiome into acetate, thus supplying lipogenic acetyl-CoA through acetyl-CoA synthetase 2 (ACSS2) but independently of ACLY. Until now, acetate was not considered a major contributor to mammalian carbon metabolism, owing to its low serum concentrations5. In strong support of this novel ‘microbiota–hepatocyte–lipogenesis’ pathway for conversion of dietary fructose, antibiotic-mediated depletion of the gut microbiome decreased acetate availability, and suppressed fructose conversion into hepatic acetyl-CoA and subsequently fatty acids. ACSS2 belongs to the ACS family of enzymes, which are evolutionarily conserved in bacteria and mammals. ACSS2-deficient mice are viable, thus suggesting that ACSS2 may support an alternative pathway that is less essential for cytosolic acetyl-CoA synthesis than the one catalysed by ACLY. Mice lacking ACSS2 show a significant decrease in body weight and in hepatic steatosis in a diet-induced-obesity model, owing to decreased dietary lipid absorption by the intestine and alterations in repartitioning and utilization of triglycerides from the adipose tissue to the liver. This phenoype is caused by decreased expression of lipid transporters and fatty-acid-oxidation genes6. To determine the contribution of ACSS2 to fructose-induced lipogenesis, the authors repressed hepatic ACSS2 in the liver in wild-type mice and in mice with liver-specific ACLY deficiency through viral gene transfer. Hepatic ACSS2 deficiency markedly suppressed lipogenesis from fructose administered via drinking water. Interestingly, ACSS2 was also required for fructose-dependent lipogenesis in the liver in wild-type mice, thus demonstrating the importance of this novel microbiome-driven pathway. ACSS2 has been reported to be under the direct positive control of SREBP1c and ChREBP in the liver in mice7. The study by Zhao et al. particularly emphasizes the correlation between fructose-containing diets and the ChREBPβ transcriptional response. The signal linking fructolysis to ChREBP and ChREBPβ activation remains a matter of debate. Hepatic ChREBP has been reported to be activated by several metabolites: G6P, xylulose-5-phosphate and/or fructose-2,6-bisphosphate8. ChREBP also undergoes several post-translational modifications in response to carbohydrates9, and fructose has been reported to stimulate ChREBP transcriptional activity through acteylation10. The work by Zhao et al.4 underlines the role of ChREBP in the regulation of fructose metabolism and underscores the need for better understanding of its regulation by this sugar.

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Fig. 1: A novel microbiota–hepatocyte–lipogenesis pathway is required for conversion of dietary fructose.

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  1. Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France

    Catherine Postic

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Correspondence to Catherine Postic.

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Postic, C. Conversion of a dietary fructose: new clues from the gut microbiome. Nat Metab 2, 217–218 (2020). https://doi.org/10.1038/s42255-020-0185-x

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