Excessive fructose consumption in Western diets correlates with increases in obesity, insulin resistance, kidney disease, and non-alcoholic fatty liver disease (NAFLD), collectively part of metabolic syndrome (MBS). Liver and kidneys metabolize 50-70% of ingested fructose, but the fate of remaining fructose remains poorly understood. Moreover, the correlation of fructose ingestion with MBS highlights the need for better understanding of whole-body fructose metabolism, in both health and disease. To that end, valid rodent models for fructose metabolism must reflect the same metabolism in humans. A serious autosomal recessive defect in fructose metabolism, called hereditary fructose intolerance (HFI), is caused by mutations in the aldolase B gene (ALDOB, human; Aldo2, mouse). With low levels of fructose exposure, HFI patients develop NAFLD and liver fibrosis, sharing pathologies with MBS. Targeting Aldo2 for deletion in mice (Aldo2-/-) provides a major step in validating that fructose metabolism in mice mimics that in humans. Like HFI patients, Aldo2-/- mice exposed to chronic, low-level dietary fructose show failure to thrive, liver dysfunction, and potential mortality. The fructose-induced symptoms of HFI and MBS result from flux through the ketohexokinase (KHK)-mediated pathway, and the metabolite Fru 1-P. Bioinformatic analysis reveals gene expression for this pathway is highest in liver, as expected; surprisingly, brain is predicted to have expression levels similar to kidney. This predicted gene expression is validated via RNA in situ hybridization, quantification of enzyme activities, presence of transport proteins, and measuring fructose oxidation rates in adult mice brains. Within the brain, regions of the cerebellum, hippocampus, cortex, and olfactory bulb show the highest population of cells expressing Fru-1-P pathway genes. In these regions, enzyme activities for both KHK and aldolase, and rates of fructolytic flux, are many times that seen in liver slices. Additionally, brains of mice on a high fructose diet show a three-fold increase in KHK activity. This suggests that not only are these regions of the brain capable of metabolizing fructose, but that they are also capable of responding to increases in dietary fructose. This work provides a foundation for research of long-term consequences of excessive fructose consumption in multiple organs. / 2017-06-21T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/17053 |
| Date | 21 June 2016 |
| Creators | Oppelt, Sarah Ann |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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