Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum

Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
Molecular Brain Research (Impact Factor: 2). 01/2006; 142(2):115-22. DOI: 10.1016/j.molbrainres.2005.09.019
Source: PubMed


Since 1967, fructose has become the primary commercial sweetener in the food industry. Large amounts of fructose can be toxic and have been correlated with atherosclerosis, malabsorption, hyperuricemia, lactic acidosis, and cataracts. To understand the deleterious and critical role(s) fructose plays in normal metabolism, it is essential to know how and where fructose is metabolized. The fructose transporter, GLUT5, and the specialized enzymes ketohexokinase, aldolase, and triokinase comprise the well-defined fructose-specific metabolic pathway found in liver, kidney, and small intestine. It is estimated that 50-70% of ingested fructose is metabolized in these tissues; where and how the remaining 30-50% is metabolized is not well defined. Prediction of tissues capable of metabolizing fructose via this pathway was done using expressed sequence tags (ESTs) in Unigene and a gene-specific virtual northern blot (VNB) algorithm. Unigene and VNB combined correctly predicted the expression of the genes required for fructose metabolism in liver, kidney, and small intestine. Both methods indicated brain, breast, lymphocytes, muscle, placenta, and stomach additionally express this set of genes. Expression of the genes for GLUT5 (glut5) and ketohexokinase (khk) in neurons was validated by immunohistochemistry and RNA in situ hybridization, respectively. Using stringent controls, clear expression of glut5 and khk was localized to Purkinje cells in the cerebellum. Cerebellum was used to oxidize fructose to carbon dioxide. Together, these data suggest that these neurons in the brain are able to utilize fructose as a carbon source.

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    • "GLUT2 and GLUT5 are distributed in the intestine, as well as in other tissues and cells. GLUT 2 is mainly expressed in the basolateral membrane of hepatocytes, kidney, small intestine, and insulin-producing β cells (Roncero et al., 2004), while GLUT 5 is expressed in the kidney, fat, skeletal muscle, brain, and sperm (Funari et al., 2005; Sasaki et al., 2004). D-Allulose might partially inhibit the uptake of D-glucose and/or D-fructose at GLUT2 or GLUT5 in those tissues and cells. "
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    ABSTRACT: Obesity and type 2 diabetes mellitus (T2DM) are the leading worldwide risk factors for mortality. The inextricably interlinked pathological progression from excessive weight gain, obesity, and hyperglycemia to T2DM, usually commencing from obesity, typically originates from overconsumption of sugar and high-fat diets. Although most patients require medications, T2DM is manageable or even preventable with consumption of low-calorie diet and maintaining body weight. Medicines like insulin, metformin, and thiazolidinediones that improve glycemic control; however, these are associated with weight gain, high blood pressure and dyslipidemia. These situations warrant attentive consideration of the role of balanced foods. Recently, we have discovered advantages of a rare sugar, d-allulose, a zero-calorie functional sweetener having strong anti-hyperlipidemic and anti-hyperglycemic effects. Study revealed that after oral administration in rats d-allulose readily entered the blood stream and was eliminated into urine within 24 hours. Cell culture study showed that d-allulose enters into and leaves the intestinal enterocytes via glucose transporters GLUT5 and GLUT2, respectively. In addition to d-allulose's short-term effects, characterization of long-term effects has been focused on preventing commencement and progression of T2DM in diabetic rats. Human trials showed that d-allulose attenuates postprandial glucose levels in healthy subjects and in borderline diabetic subjects. The anti-hyperlipidemic effect of d-allulose, combined with its anti-inflammatory actions on adipocytes is beneficial for prevention of both obesity and atherosclerosis, and is accompanied by improvements in insulin resistance and impaired glucose tolerance. Therefore, this review presents brief discussions focusing on physiological functions and potential benefits of d-allulose on obesity and T2DM. Copyright © 2015. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 08/2015; DOI:10.1016/j.pharmthera.2015.08.004 · 9.72 Impact Factor
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    • "The rate-limiting enzyme of fructolysis is ketohexokinase (KHK) which phosphorylates and converts fructose to fructose-1-phosphate for pyruvate generation. Genes that required for fructose metabolism are expressed in the neurons [10], indicating neurons in the brain are able to utilize fructose as a carbon source of ATP production. In hippocampal region, it was reported that energy generated via fructolysis sustains neuronal integrity in the absence of glucose [11,12]. "
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    ABSTRACT: The increase in fructose ingestion has been linked to overdrive of sympathetic activity and hypertension associated with the metabolic syndrome. The premotor neurons for generation of sympathetic vasomotor activity reside in the rostral ventrolateral medulla (RVLM). Activation of RVLM results in sympathoexcitation and hypertension. Neurons in the central nervous system are able to utilize fructose as a carbon source of ATP production. We examined in this study whether fructose affects ATP content in RVLM and its significance in the increase in central sympathetic outflow and hypertension induced by the high fructose diet (HFD). In normotensive rats fed with high fructose diet (HFD) for 12 weeks, there was a significant increase in tissue ATP content in RVLM, accompanied by the increases in the sympathetic vasomotor activity and blood pressure. These changes were blunted by intracisternal infusion of an ATP synthase inhibitor, oligomycin, to the HFD-fed animals. In the catecholaminergic-containing N2a cells, fructose dose-dependently upregulated the expressions of glucose transporter 2 and 5 (GluT2, 5) and the rate-limiting enzyme of fructolysis, ketohexokinase (KHK), leading to the increases in pyruvate and ATP production, as well as the release of the neurotransmitter, dopamine. These cellular events were significantly prevented after the gene knocking down by lentiviral transfection of small hairpin RNA against KHK. These results suggest that increases in ATP content in RVLM may be engaged in the augmented sympathetic vasomotor activity and hypertension associated with the metabolic syndrome induced by the HFD. At cellular level, the increase in pyruvate levels via fructolysis is involved in the fructose-induced ATP production and the release of neurotransmitter.
    Journal of Biomedical Science 01/2014; 21(1):8. DOI:10.1186/1423-0127-21-8 · 2.76 Impact Factor
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    • "However, it is important to note that neither neuron-rich rat brain primary cultures, nor rat glioma cells, can be cultured in the sorbitol-containing medium in the absence of glucose (48). The whole-brain studies by Chain et al. (1969) (51), and more recently the cerebellum by Funari et al. (2005) (59), used tissue slices that intentionally ignore the BBB. Together these studies showed a well-developed ability for the degradation and utilization of fructose by brain tissues. "
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    ABSTRACT: Under normal physiological conditions, the brain utilizes only a small number of carbon sources for energy. Recently, there is growing molecular and biochemical evidence that other carbon sources, including fructose, may play a role in neuro-energetics. Fructose is the number one commercial sweetener in Western civilization with large amounts of fructose being toxic, yet fructose metabolism remains relatively poorly characterized. Fructose is purportedly metabolized via either of two pathways, the fructose-1-phosphate pathway and/or the fructose-6-phosphate pathway. Many early metabolic studies could not clearly discriminate which of these two pathways predominates, nor could they distinguish which cell types in various tissues are capable of fructose metabolism. In addition, the lack of good physiological models, the diet-induced changes in gene expression in many tissues, the involvement of multiple genes in multiple pathways involved in fructose metabolism, and the lack of characterization of some genes involved in fructose metabolism have complicated our understanding of the physiological role of fructose in neuro-energetics. A recent neuro-metabolism study of the cerebellum demonstrated fructose metabolism and co-expression of the genes specific for the fructose 1-phosphate pathway, GLUT5 (glut5) and ketohexokinase (khk), in Purkinje cells suggesting this as an active pathway in specific neurons? Meanwhile, concern over the rapid increase in dietary fructose, particularly among children, has increased awareness about how fructose is metabolized in vivo and what effects a high fructose diet might have. In this regard, establishment of cellular and molecular studies and physiological characterization of the important and/or deleterious roles fructose plays in the brain is critical. This review will discuss the status of fructose metabolism in the brain with special reference to the cerebellum and the physiological roles of the different pathways.
    The Cerebellum 02/2007; 6(2):130-40. DOI:10.1080/14734220601064759 · 2.72 Impact Factor
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