First published March 1, 2018 - More info
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
Samir Softic, Manoj K. Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T. O’Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B. Newgard, David E. Cohen, C. Ronald Kahn
Original citation: J Clin Invest. 2017;127(11):4059–4074. https://doi.org/10.1172/JCI94585
Citation for this corrigendum: J Clin Invest. 2018;128(3):1199. https://doi.org/10.1172/JCI99009
Following publication of this article, the authors became aware that reference 22 was not accurately described in Results. The corrected paragraph that pertains to this reference appears below.
ChREBP has many overlapping functions with SREBP1c, as both have been reported to increase expression of lipogenic genes, such as Fasn and Acaca (20). ChREBP has also been shown to induce fibroblast growth factor 21 (Fgf21), which can regulate fatty acid oxidation (21). In the current study, we observed increased expression of fatty acid oxidation genes in animals fed HFD+Gluc compared with HFD+Fruct in concert with increased expression of total ChREBP (Figures 3D and 4D). However, ChREBP has actually been shown to decrease expression of the key fatty acid oxidation gene CPT1a (22), and our study did not include measures of direct transcriptional activation. Thus, the general increase in fatty acid oxidation genes observed with feeding of HFD+Gluc, including increases in carnitine palmitoyltransferase 2 (Cpt2), family member 12, medium, long, and very long chain acyl–coenzyme A dehydrogenase (Acad12, Acadm, Acadl, Acadvl), acetyl–coenzyme A acyltransferase 2 (Acaa2), and the α and β subunits of hydroxyacyl–coenzyme A dehydrogenase (Hadha and Hadhb), cannot be ascribed to ChREBP. Further studies will be required to fully understand the relevant regulatory networks mediating increased expression of enzymes regulating fatty acid oxidation in mice on HFD+Gluc. However, what is clear is that glucose as compared to fructose supplementation of HFD induces very different programs of metabolic regulation in liver, reflecting both complex transcriptional and posttranscriptional regulation.
During the preparation of the manuscript, Figure 2D was inadvertently mislabeled by the journal. The corrected figure part is below.
The authors regret the error.
See the related article at Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.