Aerobic exercise prevents cardiomyocyte damage caused by oxidative stress in early cardiovascular disease by increasing vascularity while L-arginine supplementation prevents it by increasing activation of the enzyme nitric oxide synthase.

L-Arginine and chronic exercise reduce oxidative stress. However, it is unclear how they affect cardiomyocytes during cardiovascular disease (CVD) development. The aim of this research was to investigate the possible effects of L-arginine supplementation and aerobic training on systemic oxidative stress and their consequences on cardiomyocytes during cardiometabolic disease onset caused by excess fructose. Wistar rats were allocated into four groups: control (C), fructose (F, 10% fructose in water), fructose training (FT; moderate running, 50-70% of the maximal velocity), and fructose arginine (FA; 880 mg/kg/day). Fructose was given for two weeks and fructose plus treatments for the subsequent eight weeks. Body composition, blood glucose, insulin, lipid profile, lipid peroxidation, nitrite, metalloproteinase-2 (MMP-2) activity, left ventricle histological changes, microRNA-126, -195, and -146, eNOS, p-eNOS, and TNF-α expressions were analyzed. Higher abdominal fat mass, triacylglycerol level, and insulin level were observed in the F group, and both treatments reversed these alterations. Myocardial vascularization was impaired in fructose-fed groups, except in FT. Cardiomyocyte hypertrophy was observed in all fructose-fed groups. TNF-α levels were higher in fructose-fed groups than in the C group, and p-eNOS levels were higher in the FA than in the C and F groups. Lipid peroxidation was higher in the F group than in the FT and C groups. During CVD onset, moderate aerobic exercise reduced lipid peroxidation, and both training and L-arginine prevented metabolic changes caused by excessive fructose. Myocardial vascularization was impaired by fructose, and cardiomyocyte hypertrophy appeared to be influenced by pro-inflammatory and oxidative environments.

Fructose Metabolism and Metabolic Dysfunction in Adolescents and Young Adults.

There is a worldwide epidemic of obesity and its associated metabolic dysfunction [...].

Determinants of sugar-induced influx in the mammalian fructose transporter GLUT5.

In mammals, glucose transporters (GLUT) control organism-wide blood-glucose homeostasis. In human, this is accomplished by 14 different GLUT isoforms, that transport glucose and other monosaccharides with varying substrate preferences and kinetics. Nevertheless, there is little difference between the sugar-coordinating residues in the GLUT proteins and even the malarial Plasmodium falciparum transporter PfHT1, which is uniquely able to transport a wide range of different sugars. PfHT1 was captured in an intermediate 'occluded' state, revealing how the extracellular gating helix TM7b has moved to break and occlude the sugar-binding site. Sequence difference and kinetics indicated that the TM7b gating helix dynamics and interactions likely evolved to enable substrate promiscuity in PfHT1, rather than the sugar-binding site itself. It was unclear, however, if the TM7b structural transitions observed in PfHT1 would be similar in the other GLUT proteins. Here, using enhanced sampling molecular dynamics simulations, we show that the fructose transporter GLUT5 spontaneously transitions through an occluded state that closely resembles PfHT1. The coordination of D-fructose lowers the energetic barriers between the outward- and inward-facing states, and the observed binding mode for D-fructose is consistent with biochemical analysis. Rather than a substrate-binding site that achieves strict specificity by having a high affinity for the substrate, we conclude GLUT proteins have allosterically coupled sugar binding with an extracellular gate that forms the high-affinity transition-state instead. This substrate-coupling pathway presumably enables the catalysis of fast sugar flux at physiological relevant blood-glucose concentrations.

Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells.

BACKGROUND: Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood. METHODS: Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD). RESULTS: We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens. CONCLUSIONS: These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.

The fructose survival hypothesis for obesity.

The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) that aims to protect animals in advance of crisis. The response is characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation and increased blood pressure. The process is initiated by the ingestion of fructose or by stimulating endogenous fructose production via the polyol pathway. Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, the inhibition of AMP kinase and stimulation of vasopressin. Mitochondrial oxidative phosphorylation is suppressed, and glycolysis stimulated. While this response is aimed to be modest and short-lived, the response in humans is exaggerated due to gain of 'thrifty genes' coupled with a western diet rich in foods that contain or generate fructose. We propose excessive fructose metabolism not only explains obesity but the epidemics of diabetes, hypertension, non-alcoholic fatty liver disease, obesity-associated cancers, vascular and Alzheimer's dementia, and even ageing. Moreover, the hypothesis unites current hypotheses on obesity. Reducing activation and/or blocking this pathway and stimulating mitochondrial regeneration may benefit health-span. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Bean Leaves Ameliorate Lipotoxicity in Fatty Liver Disease.

Bioactive compounds in plant-based food have protective effects against metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Bean leaves are widely cultivated in the world and are a source of dietary fiber and polyphenols. High fat/high fructose diet animal models promote deleterious effects in adipose and non-adipose tissues (lipotoxicity), leading to obesity and its comorbidities. Short-term supplementation of bean leaves exhibited anti-diabetic, anti-hyperlipidemic, and anti-obesity effects in high-fat/high-fructose diet animal models. This study aimed to evaluate the effect of bean leaves supplementation in the prevention of lipotoxicity in NAFLD and contribute to elucidating the possible mechanism involved for a longer period of time. During thirteen weeks, male Wistar rats (n = 9/group) were fed with: (1) S: Rodent Laboratory Chow 5001® (RLC); (2) SBL: 90% RLC+ 10% dry bean leaves; (3) H: high-fat/high-fructose diet; (4) HBL: H+ 10% of dry bean leaves. Overall, a HBL diet enhanced impaired glucose tolerance and ameliorated obesity, risk factors in NAFLD development. Additionally, bean leaves exerted antioxidant (↑serum GSH) and anti-inflammatory (↓mRNA TNFα in the liver) effects, prevented hepatic fat accumulation by enhanced ↑mRNA PPARα (ß oxidation), and enhanced lipid peroxidation (↓liver MDA). These findings suggest that bean leaves ameliorated hepatic lipotoxicity derived from the consumption of a deleterious diet.

Lactate formation from fructose or C1 compounds in the acetogen Acetobacterium woodii by metabolic engineering.

Anaerobic, acetogenic bacteria are promising biocatalysts for a sustainable bioeconomy since they capture and convert carbon dioxide to acetic acid. Hydrogen is an intermediate in acetate formation from organic as well as C1 substrates. Here, we analyzed mutants of the model acetogen Acetobacterium woodii in which either one of the two hydrogenases or both together were genetically deleted. In resting cells of the double mutant, hydrogen formation from fructose was completely abolished and carbon was redirected largely to lactate. The lactate/fructose and lactate/acetate ratios were 1.24 and 2.76, respectively. We then tested for lactate formation from methyl groups (derived from glycine betaine) and carbon monoxide. Indeed, also under these conditions lactate and acetate were formed in equimolar amounts with a lactate/acetate ratio of 1.13. When the electron-bifurcating lactate dehydrogenase/ETF complex was genetically deleted, lactate formation was completely abolished. These experiments demonstrate the capability of A. woodii to produce lactate from fructose but also from promising C1 substrates, methyl groups and carbon monoxide. This adds an important milestone towards generation of a value chain leading from CO2 to value-added compounds. KEY POINTS: • Resting cells of the ΔhydBA/hdcr mutant of Acetobacterium woodii produced lactate from fructose or methyl groups + CO • Lactate formation from methyl groups + CO was completely abolished after deletion of lctBCD • Metabolic engineering of a homoacetogen to lactate formation gives a potential for industrial applications.

Long-term high fructose intake promotes lacrimal gland dysfunction by inducing gut dysbiosis in mice.

The lacrimal gland is essential for maintaining ocular surface health through the secretion of the aqueous layer of the tear film. It is therefore important to explore the intrinsic and extrinsic factors that affect the structure and function of the lacrimal gland and the mechanisms underlying them. With the prevalence of Westernized diets characterized by high sugar and fat content, the susceptibility to many diseases, including ocular diseases, is increased by inducing dysbiosis of the gut microbiome. Here, we found that the composition, abundance, and diversity of the gut microbiome was significantly altered in mice by drinking 15% high fructose water for one month, as determined by 16S rRNA sequencing. This was accompanied by a significant increase in lipid deposition and inflammatory cell infiltration in the extraorbital lacrimal glands (ELGs) of mice. Transcriptome analysis based on bulk RNA-sequencing revealed abnormal activation of some of several metabolic and immune-related pathways. In addition, the secretory response to stimulation with the cholinergic receptor agonist pilocarpine was significantly reduced. However, when the composition and diversity of the gut microbiome of high fructose intake (HFI)-treated mice were improved by transplanting feces from normal young healthy mice, the pathological alterations in ELG structure, inflammatory cell infiltration, secretory function and transcriptome analysis described above were significantly reversed compared to age-matched control mice. In conclusion, our data suggest that prolonged HFI may cause pathological damage to the structure and function of the ELG through the induction of gut dysbiosis. Restoration of intestinal dysbiosis in HFI-treated mice by fecal transplantation has a potential role in ameliorating these pathological impairments.

The transport of mannitol in Sinorhizobium meliloti is carried out by a broad-substrate polyol transporter SmoEFGK and is affected by the ability to transport and metabolize fructose.

The smo locus (sorbitol mannitol oxidation) is found on the chromosome of S. meliloti's tripartite genome. Mutations at the smo locus reduce or abolish the ability of the bacterium to grow on several carbon sources, including sorbitol, mannitol, galactitol, d-arabitol and maltitol. The contribution of the smo locus to the metabolism of these compounds has not been previously investigated. Genetic complementation of mutant strains revealed that smoS is responsible for growth on sorbitol and galactitol, while mtlK restores growth on mannitol and d-arabitol. Dehydrogenase assays demonstrate that SmoS and MtlK are NAD+-dependent dehydrogenases catalysing the oxidation of their specific substrates. Transport experiments using a radiolabeled substrate indicate that sorbitol, mannitol and d-arabitol are primarily transported into the cell by the ABC transporter encoded by smoEFGK. Additionally, it was found that a mutation in either frcK, which is found in an operon that encodes the fructose ABC transporter, or a mutation in frk, which encodes fructose kinase, leads to the induction of mannitol transport.

New structures of Class II Fructose-1,6-Bisphosphatase from Francisella tularensis provide a framework for a novel catalytic mechanism for the entire class.

Class II Fructose-1,6-bisphosphatases (FBPaseII) (EC: 3.1.3.11) are highly conserved essential enzymes in the gluconeogenic pathway of microorganisms. Previous crystallographic studies of FBPasesII provided insights into various inactivated states of the enzyme in different species. Presented here is the first crystal structure of FBPaseII in an active state, solved for the enzyme from Francisella tularensis (FtFBPaseII), containing native metal cofactor Mn2+ and complexed with catalytic product fructose-6-phosphate (F6P). Another crystal structure of the same enzyme complex is presented in the inactivated state due to the structural changes introduced by crystal packing. Analysis of the interatomic distances among the substrate, product, and divalent metal cations in the catalytic centers of the enzyme led to a revision of the catalytic mechanism suggested previously for class II FBPases. We propose that phosphate-1 is cleaved from the substrate fructose-1,6-bisphosphate (F1,6BP) by T89 in a proximal α-helix backbone (G88-T89-T90-I91-T92-S93-K94) in which the substrate transition state is stabilized by the positive dipole of the 〈-helix backbone. Once cleaved a water molecule found in the active site liberates the inorganic phosphate from T89 completing the catalytic mechanism. Additionally, a crystal structure of Mycobacterium tuberculosis FBPaseII (MtFBPaseII) containing a bound F1,6BP is presented to further support the substrate binding and novel catalytic mechanism suggested for this class of enzymes.

Effects of Fructose and Palmitic Acid on Gene Expression in Drosophila melanogaster Larvae: Implications for Neurodegenerative Diseases.

One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common alterations are cardiovascular diseases, and a high correlation between overnutrition and neurodegenerative diseases has also been found. The urgency in the study of specific damage to tissues such as the brain and intestine led us to use Drosophila melanogaster to study the metabolic effects caused by the consumption of fructose and palmitic acid in specific tissues. Thus, third instar larvae (96 ± 4 h) of the wild Canton-S strain of D. melanogaster were used to perform transcriptomic profiling in brain and midgut tissues to test for the potential metabolic effects of a diet supplemented with fructose and palmitic acid. Our data infer that this diet can alter the biosynthesis of proteins at the mRNA level that participate in the synthesis of amino acids, as well as fundamental enzymes for the dopaminergic and GABAergic systems in the midgut and brain. These also demonstrated alterations in the tissues of flies that may help explain the development of various reported human diseases associated with the consumption of fructose and palmitic acid in humans. These studies will not only help to better understand the mechanisms by which the consumption of these alimentary products is related to the development of neuronal diseases but may also contribute to the prevention of these conditions.

Dietary sugars silence the master regulator of carbohydrate utilization in human gut Bacteroides species.

The mammalian gut microbiota is a critical human health determinant with therapeutic potential for remediation of many diseases. The host diet is a key factor governing the gut microbiota composition by altering nutrient availability and supporting the expansion of distinct microbial populations. Diets rich in simple sugars modify the abundance of microbial subsets, enriching for microbiotas that elicit pathogenic outcomes. We previously demonstrated that diets rich in fructose and glucose can reduce the fitness and abundance of a human gut symbiont, Bacteroides thetaiotaomicron, by silencing the production of a critical intestinal colonization protein, called Roc, via its mRNA leader through an unknown mechanism. We have now determined that dietary sugars silence Roc by reducing the activity of BT4338, a master regulator of carbohydrate utilization. Here, we demonstrate that BT4338 is required for Roc synthesis, and that BT4338 activity is silenced by glucose or fructose. We show that the consequences of glucose and fructose on orthologous transcription factors are conserved across human intestinal Bacteroides species. This work identifies a molecular pathway by which a common dietary additive alters microbial gene expression in the gut that could be harnessed to modulate targeted microbial populations for future therapeutic interventions.

[6,6'-2 H2 ] fructose as a deuterium metabolic imaging probe in liver cancer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Imaging plays a crucial role in the early detection of HCC, although current methods are limited in their ability to characterize liver lesions. Most recently, deuterium metabolic imaging (DMI) has been demonstrated as a powerful technique for the imaging of metabolism in vivo. Here, we assess the metabolic flux of [6,6'-2 H2 ] fructose in cell cultures and in subcutaneous mouse models at 9.4 T. We compare these rates with the most widely used DMI probe, [6,6'-2 H2 ] glucose, exploring the possibility of developing 2 H fructose to overcome the limitations of glucose as a novel DMI probe for detecting liver tumors. Comparison of the in vitro metabolic rates implies their similar glycolytic metabolism in the TCA cycle due to comparable production rates of 2 H glutamate/glutamine (glx) for the two precursors, but overall higher glycolytic metabolism from 2 H glucose because of a higher production rate of 2 H lactate. In vivo kinetic studies suggest that HDO can serve as a robust reporter for the consumption of the precursors in liver tumors. As fructose is predominantly metabolized in the liver, deuterated water (HDO) produced from 2 H fructose is probably less contaminated from whole-body metabolism in comparison with glucose. Moreover, in studies of the normal liver, 2 H fructose is readily converted to 2 H glx, enabling the characterization of 2 H fructose kinetics. This overcomes a major limitation of previous 2 H glucose studies in the liver, which were unable to confidently discern metabolic flux due to overlapped signals of 2 H glucose and its metabolic product, 2 H glycogen. This suggests a unique role for 2 H fructose metabolism in HCC and the normal liver, making it a useful approach for assessing liver-related diseases and the progression to oncogenesis.

Maternal Intake of Either Fructose or the Artificial Sweetener Acesulfame-K Results in Differential and Sex-Specific Alterations in Markers of Skin Inflammation and Wound Healing Responsiveness in Mouse Offspring: A Pilot Study.

Growing evidence has demonstrated that maternal artificial sweetener (AS) consumption may not be a beneficial alternative when compared to sugar-sweetened beverages and potentially leads to metabolic dysfunction in adult offspring. Compromised skin integrity and wound healing associated with type 2 diabetes can lead to complications such as diabetic pressure injury (PI). In this context, the skin plays an important role in the maintenance of metabolic homeostasis, yet there is limited information on the influence of sugar- or AS-sweetened beverages during pregnancy on developmental programming and offspring skin homeostasis. This study examined the impact of maternal fructose or acesulfame-k consumption on offspring wound healing. Female C57Bl/6 mice received a chow diet ad libitum with either water (CD), fructose (FR; 34.7 mM fructose), or AS (AS; 12.5 mM Acesulfame-K) throughout pregnancy and lactation. PIs were induced in offspring at 9 weeks of age (n = 6/sex/diet). PIs and healthy skin biopsies were collected for later analysis. Maternal AS intake increased skin inflammatory markers in healthy biopsies while an FR diet increased Tgfb expression, and both diets induced subtle changes in inflammatory markers post-wound inducement in a sex-specific manner. Furthermore, a maternal FR diet had a significant effect on pressure wound severity and early wound healing delay, while AS maternal diet had a sex-specific effect on the course of the healing process. This study demonstrates the need for a better understanding of developmental programming as a mediator of later-life skin integrity and wound responsiveness.

Ishige okamurae Celluclast extract ameliorates non-alcoholic fatty liver in high-fructose diet-fed mice by modulation of lipid metabolism and gut microbiota composition.

Recently, a new mechanism has revealed that gut microbiota plays a pivotal role in metabolizing fructose to acetate that facilitates hepatic lipogenesis. Therefore, our study investigated the role of microbiome on abnormal lipid synthesis in the presence of fructose and identified attenuating effects of Ishige okamurae Celluclast extract (IOCE) against fructose-induced fatty liver. The results indicated that oral administration of IOCE (150 and 300 mg/kg/day for 12 weeks) significantly reduced both gut microbiota-mediated and -non-mediated hepatic lipogenesis simultaneously triggered by fructose metabolism. IOCE reduced hepatic triglyceride accumulation and expression levels of key enzymes for glucolipid metabolism. In addition, IOCE regulated fatty acid synthesis, ß-oxidation, and improved hepatic inflammation. Furthermore, IOCE inhibited direct fructose-to-acetate conversion and altered the compositions of gut microbiota. These findings suggest that IOCE might serve as a potential prebiotic dietary supplement by ameliorating fatty liver through dual regulation of classical lipogenic pathway and gut microbiota.

Discovery of a novel transcriptional regulator of sugar catabolism in archaea.

The haloarchaeon Haloferax volcanii degrades D-glucose via the semiphosphorylative Entner-Doudoroff pathway and D-fructose via a modified Embden-Meyerhof pathway. Here, we report the identification of GfcR, a novel type of transcriptional regulator that functions as an activator of both D-glucose and D-fructose catabolism. We find that in the presence of D-glucose, GfcR activates gluconate dehydratase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase and also acts as activator of the phosphotransferase system and of fructose-1,6-bisphosphate aldolase, which are involved in uptake and degradation of D-fructose. In addition, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase are activated by GfcR in the presence of D-fructose and also during growth on D-galactose and glycerol. Electrophoretic mobility shift assays indicate that GfcR binds directly to promoters of regulated genes. Specific intermediates of the degradation pathways of the three hexoses and of glycerol were identified as inducer molecules of GfcR. GfcR is composed of a phosphoribosyltransferase (PRT) domain with an N-terminal helix-turn-helix motif and thus shows homology to PurR of Gram-positive bacteria that is involved in the transcriptional regulation of nucleotide biosynthesis. We propose that GfcR of H. volcanii evolved from a PRT-like enzyme to attain a function as a transcriptional regulator of central sugar catabolic pathways in archaea.

CcpA and CodY Regulate CRISPR-Cas System of Streptococcus mutans.

Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes are widely recognized as bacterial adaptive immune systems against invading viruses and bacteriophages. The oral pathogen Streptococcus mutans encodes two CRISPR-Cas loci (CRISPR1-Cas and CRISPR2-Cas), and their expression under environmental conditions is still under investigation. In this study, we investigated the transcriptional regulation of cas operons by CcpA and CodY, two global regulators that contribute to carbohydrate and (p)ppGpp metabolism. The possible promoter regions for cas operons and the binding sites for CcpA and CodY in the promoter regions of both CRISPR-Cas loci were predicted using computational algorithms. We found that CcpA could directly bind to the upstream region of both cas operons, and detected an allosteric interaction of CodY within the same region. The binding sequences of the two regulators were identified through footprinting analysis. Our results showed that the promoter activity of CRISPR1-Cas was enhanced under fructose-rich conditions, while deletion of the ccpA gene led to reduced activity of the CRISPR2-Cas promoter under the same conditions. Additionally, deletion of the CRISPR systems resulted in a significant decrease in fructose uptake ability compared to the parental strain. Interestingly, the accumulation of guanosine tetraphosphate (ppGpp) was reduced in the presence of mupirocin, which induces a stringent response, in the CRISPR1-Cas-deleted (ΔCR1cas) and both CRISPR-Cas-deleted (ΔCRDcas) mutant strains. Furthermore, the promoter activity of both CRISPRs was enhanced in response to oxidative or membrane stress, while the CRISPR1 promoter activity was reduced under low-pH conditions. Collectively, our findings demonstrate that the transcription of the CRISPR-Cas system is directly regulated by the binding of CcpA and CodY. These regulatory actions play a crucial role in modulating glycolytic processes and exerting effective CRISPR-mediated immunity in response to nutrient availability and environmental cues. IMPORTANCE An effective immune system has evolved not only in eukaryotic organisms but also in microorganisms, enabling them to rapidly detect and neutralize foreign invaders in the environment. Specifically, the CRISPR-Cas system in bacterial cells is established through a complex and sophisticated regulatory mechanism involving specific factors. In this study, we demonstrate that the expression of two CRISPR systems in S. mutans can be controlled by two global regulators, CcpA and CodY, which play critical roles in carbohydrate metabolism and amino acid biosynthesis. Importantly, our results show that the expression of the CRISPR-Cas system in S. mutans influences (p)ppGpp production during the stringent response, which is a gene expression regulatory response that aids in environmental stress adaptation. This transcriptional regulation by these regulators enables a CRISPR-mediated immune response in a host environment with limited availability of carbon sources or amino acids, while ensuring efficient carbon flux and energy expenditure to support multiple metabolic processes.

High Fructose Corn Syrup Accelerates Kidney Disease and Mortality in Obese Mice with Metabolic Syndrome.

The presence of obesity and metabolic syndrome is strongly linked with chronic kidney disease (CKD), but the mechanisms responsible for the association are poorly understood. Here, we tested the hypothesis that mice with obesity and metabolic syndrome might have increased susceptibility to CKD from liquid high fructose corn syrup (HFCS) by favoring the absorption and utilization of fructose. We evaluated the pound mouse model of metabolic syndrome to determine if it showed baseline differences in fructose transport and metabolism and whether it was more susceptible to chronic kidney disease when administered HFCS. Pound mice have increased expression of fructose transporter (Glut5) and fructokinase (the limiting enzyme driving fructose metabolism) associated with enhanced fructose absorption. Pound mice receiving HFCS rapidly develop CKD with increased mortality rates associated with intrarenal mitochondria loss and oxidative stress. In pound mice lacking fructokinase, the effect of HFCS to cause CKD and early mortality was aborted, associated with reductions in oxidative stress and fewer mitochondria loss. Obesity and metabolic syndrome show increased susceptibility to fructose-containing sugars and increased risk for CKD and mortality. Lowering added sugar intake may be beneficial in reducing the risk for CKD in subjects with metabolic syndrome.

Impacts of High Fructose Diet and Chronic Exercise on Nitric Oxide Synthase and Oxidative Stress in Rat Kidney.

Chronic exercise (Ex) exerts antihypertensive and renoprotective effects in rats fed a high fructose diet (HFr). To elucidate the mechanisms, the impacts of an HFr and Ex on the nitric oxide (NO) system and oxidative stress in the kidney were examined. Rats were fed a control diet or an HFr, and a part of the HFr-fed rats underwent treadmill running for 12 weeks. The HFr did not affect nitrate/nitrite (NOx) levels in plasma and urine, and Ex increased the NOx levels. The HFr increased thiobarbituric acid reactive substance (TBARS) levels in plasma and urine, and Ex decreased the HFr-increased TBARS levels in plasma. The HFr increased the neuronal and endothelial NO synthase (nNOS and eNOS) expressions, and Ex enhanced the HFr-increased eNOS expression. The HFr inhibited the eNOS phosphorylation at serine 1177, and Ex restored the HFr-inhibited eNOS phosphorylation. The HFr increased xanthine oxidase and NADPH oxidase activities, and Ex restored the HFr-increased xanthine oxidase activity but enhanced the HFr-increased NADPH oxidase activity. The HFr increased the nitrotyrosine levels, and Ex attenuated the HFr-increased levels. These results indicate that although Ex enhances the HFr-increased eNOS expression and NADPH oxidase activity, an HFr inhibits renal eNOS phosphorylation and NO bioavailability, whereas Ex ameliorates them.