Evidence for Toxic Advanced Glycation End-Products Generated in the Normal Rat Liver

Glucose/fructose in beverages/foods containing high-fructose corn syrup (HFCS) are metabolized to glyceraldehyde (GA) in the liver. We previously reported that GA-derived advanced glycation end-products (toxic AGEs, TAGE) are generated and may induce the onset/progression of non-alcoholic fatty liver disease (NAFLD). We revealed that the generation of TAGE in the liver and serum TAGE levels were higher in NAFLD patients than in healthy humans. Although we propose the intracellular generation of TAGE in the normal liver, there is currently no evidence to support this, and the levels of TAGE produced have not yet been measured. In the present study, male Wister/ST rats that drank normal water or 10% HFCS 55 (HFCS beverage) were maintained for 13 weeks, and serum TAGE levels and intracellular TAGE levels in the liver were analyzed. Rats in the HFCS group drank 127.4 mL of the HFCS beverage each day. Serum TAGE levels and intracellular TAGE levels in the liver both increased in the HFCS group. A positive correlation was observed between intracellular TAGE levels in the liver and serum TAGE levels. On the other hand, in male Wister/ST rats that drank Lactobacillus beverage for 12 weeks—a commercial drink that contains glucose, fructose, and sucrose— no increases were observed in intracellular TAGE or serum TAGE levels. Intracellular TAGE were generated in the normal rat liver, and their production was promoted by HFCS, which may increase the risk of NAFLD.

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The Association Between Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Dysfunction Explained by Non-Alcoholic Fatty Liver Disease; A 7-year Follow-up of the CODAM Study

MaRBLe ◽

10.26481/marble.2015.v6.369 ◽

2016 ◽

Vol 6 ◽

Author(s):

Johnny De Nóbrega Teixeira

Keyword(s):

Liver Disease ◽

Advanced Glycation End Products ◽

Fatty Liver Disease ◽

Soluble Receptor ◽

Advanced Glycation ◽

Alcoholic Fatty Liver ◽

Glycation End Products ◽

End Products ◽

Alcoholic Fatty Liver Disease

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The Effect of Advanced Glycation End-Products and Aminoguanidine on Tnfα Production by Rat Peritoneal Macrophages

Peritoneal Dialysis International ◽

10.1177/089686080102100203 ◽

2001 ◽

Vol 21 (2) ◽

pp. 122-131 ◽

Cited By ~ 21

Author(s):

Gloria Rashid ◽

Ami-Ad Luzon ◽

Ze'ev Korzets ◽

Osnat Klein ◽

Ella Zeltzer ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Intraperitoneal Injection ◽

Intraperitoneal Administration ◽

Peritoneal Macrophages ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Normal Rat ◽

Daily Intraperitoneal Injection

Objective To evaluate the effect of advanced glycation end-products (AGEs) and the inhibitor of their formation, aminoguanidine, on tumor necrosis factor-α (TNFα) production (as a functional marker) by rat peritoneal macrophages (PMΦ). Design Charles River rats underwent a daily intraperitoneal injection of peritoneal dialysis solution [(PDS), 4.25 g/dL dextrose; Dialine, Travenol, Ashdod, Israel] for a 2-month period (group E). Another group of rats was subjected to the same protocol with the addition of 25 mg/kg aminoguanidine (group A). Three control groups were utilized: ( 1 ) rats that were injected daily with aminoguanidine only (group AO), ( 2 ) rats that were injected with Dulbecco's phosphate-buffered saline (group D), and ( 3 ) rats in which no intervention was carried out (group C). After 2 months, PMΦ were isolated from rat peritoneal effluent and their TNFα production measured by ELISA in cell-free culture supernatants, in both the basal state and after 24-hour stimulation with lipopolysaccharide (LPS). The concentrations of AGEs in peritoneal effluent were assayed and correlated to TNFα levels. PMΦ obtained from normal rats were then incubated for 24 hours with ( 1 ) the peritoneal effluent of each of the above respective groups, with or without LPS; ( 2 ) increasing concentrations of AGEs (0 - 250 μg/mL); and ( 3 ) increasing concentrations of aminoguanidine (0 - 7.5 mg/mL), and TNFα secretion again determined. Results After 2 months of daily intraperitoneal injection of PDS, in the basal state, TNFα production was significantly higher in PMΦ isolated from the peritoneal effluent groups (groups E, A, and AO) compared to controls (group C). Following LPS stimulation, a further increase in TNFα secretion was seen, with a significantly greater response in group AO versus groups E, A, and D. Effluent AGEs were markedly elevated only in group E. No correlation was found between TNFα secretion by these PMΦ and the concentration of AGEs. On incubation with the respective peritoneal effluents (groups E, A, and AO), in both the basal and stimulated state, TNFα production by PMΦ from normal rats was significantly enhanced compared to group C. Incubation with increasing concentrations of AGEs or aminoguanidine resulted in an increase of TNFα secretion by these PMΦ. Conclusions Following intermittent intraperitoneal administration of glucose-based PDS, rat PMΦ are chronically activated, as evidenced by increased basal TNFα secretion. The peritoneal effluent of such treated animals is capable of stimulating TNFα production by normal rat PMΦ. These data suggest that glucose-based PDS acts as a primer of PMΦ, which retain their ability to further stimulation by LPS. Although, in vitro, AGEs promote TNFα secretion by normal rat PMΦ, in vivo, their influence is probably modulated by other factors. Aminoguanidine has a specific inducing effect on rat PMΦ, independent of glucose-based PDS.

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Potential of an Interorgan Network Mediated by Toxic Advanced Glycation End-Products in a Rat Model

Nutrients ◽

10.3390/nu13010080 ◽

2020 ◽

Vol 13 (1) ◽

pp. 80

Author(s):

Shinya Inoue ◽

Takanobu Takata ◽

Yusuke Nakazawa ◽

Yuka Nakamura ◽

Xin Guo ◽

...

Keyword(s):

Gene Expression ◽

Advanced Glycation End Products ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Advanced Glycation ◽

High Fructose ◽

Glycation End Products ◽

End Products ◽

Liver And Kidney

Excessive intake of glucose and fructose in beverages and foods containing high-fructose corn syrup (HFCS) plays a significant role in the progression of lifestyle-related diseases (LSRD). Glyceraldehyde-derived advanced glycation end-products (AGEs), which have been designated as toxic AGEs (TAGE), are involved in LSRD progression. Understanding of the mechanisms underlying the effects of TAGE on gene expression in the kidneys remains limited. In this study, DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were used to investigate whether HFCS-consuming Wister rats generated increased intracellular serum TAGE levels, as well as the potential role of TAGE in liver and kidney dysfunction. HFCS consumption resulted in significant accumulation of TAGE in the serum and liver of rats, and induced changes in gene expression in the kidneys without TAGE accumulation or upregulation of receptor for AGEs (RAGE) upregulation. Changes in specific gene expression profiles in the kidney were more correlated with TAGE levels in the liver tissue than in the serum. These findings suggest a direct or indirect interaction may be present between the liver and kidneys that does not involve serum TAGE or RAGE. The involvement of internal signal transduction factors such as exosomes or cytokines without IL-1β and TNF-α is suggested to contribute to the observed changes in kidney gene expression.

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Intakes of apple juice, fruit drinks and soda are associated with prevalent asthma in US children aged 2–9 years

Public Health Nutrition ◽

10.1017/s1368980015000865 ◽

2015 ◽

Vol 19 (1) ◽

pp. 123-130 ◽

Cited By ~ 44

Author(s):

Luanne Robalo DeChristopher ◽

Jaime Uribarri ◽

Katherine L Tucker

Keyword(s):

Advanced Glycation End Products ◽

Apple Juice ◽

High Fructose Corn Syrup ◽

Advanced Glycation ◽

Corn Syrup ◽

High Fructose ◽

Glycation End Products ◽

End Products ◽

Asthma In Children ◽

Us Children

AbstractObjectiveHigh soft drink consumption has been linked with asthma. Anecdotal evidence links high-fructose corn syrup with asthma. The receptor of advanced glycation end products (RAGE) has emerged as a mediator of asthma. The objectives of the present study were to: (i) assess the correlation between intake of beverages containing excess free fructose (EFF beverages) and asthma in children; and (ii) epidemiologically test the mechanistic hypothesis that intake of high EFF beverages, such as apple juice or beverages sweetened with high-fructose corn syrup, is associated with increased risk of asthma. This hypothesis is based on the possible effect of increases in the in situ intestinal formation of advanced glycation end products (enFruAGE) with EFF, which may be absorbed and play a role in RAGE-mediated asthma.DesignWe examined cross-sectional associations between beverage intake and self-reported current or history of asthma. Exposure variables were EFF beverages, including apple juice (AJ), non-diet soft drinks (ndSD) and fruit drinks (FD). Orange juice (OJ), not an EFF beverage, was included as a comparison. Rao–Scott χ2 analysis was used for prevalence differences and logistic regression for associations, adjusted for age, sex, race/ethnicity, BMI and total energy intake.SettingData are from the National Health and Nutrition Examination Survey 2003–2006, a nationally representative survey.SubjectsUS children (n 1961) aged 2–9 years with complete responses on the dietary frequency questionnaire.ResultsIntakes of EFF beverages were significantly associated with asthma in 2–9-year-olds. Adjusted odds of asthma in children consuming EFF beverages ≥5 times/week was more than five times that in children consuming these beverages ≤1 time/month (OR=5·29, P=0·012). Children consuming AJ ≥5 times/week v. ≤1 time/month, adjusted for the other beverages, were more than twice as likely to have asthma (OR=2·43, P=0·035). In contrast, there was a tendency for OJ to be protective.ConclusionsThese results support the hypothesis that intake of high EFF beverages, including AJ and beverages sweetened with high-fructose corn syrup, is associated with asthma in children aged 2–9 years. Results support the mechanistic hypothesis that enFruAGE may be an overlooked contributor to asthma in children. Longitudinal studies are needed to provide evidence of causal association.

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Serum levels of advanced glycation end-products (AGEs) and the decoy soluble receptor for AGEs (sRAGE) can identify non-alcoholic fatty liver disease in age-, sex- and BMI-matched normo-glycemic adults

Metabolism ◽

10.1016/j.metabol.2018.01.023 ◽

2018 ◽

Vol 83 ◽

pp. 120-127 ◽

Cited By ~ 17

Author(s):

Susana A. Palma-Duran ◽

Meropi D. Kontogianni ◽

Antonis Vlassopoulos ◽

Shudong Zhao ◽

Aikaterini Margariti ◽

...

Keyword(s):

Liver Disease ◽

Advanced Glycation End Products ◽

Fatty Liver Disease ◽

Serum Levels ◽

Soluble Receptor ◽

Advanced Glycation ◽

Alcoholic Fatty Liver ◽

Glycation End Products ◽

End Products ◽

Alcoholic Fatty Liver Disease

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Association of Dietary Fructose With Serum Advanced Glycation End Products in a Controlled Feeding Study of Healthy Adults

Current Developments in Nutrition ◽

10.1093/cdn/nzab033_065 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 65-65

Author(s):

Bethany Weigand ◽

Susana A. Palma-Duran ◽

Karen Sweazea ◽

Chong Lee ◽

Natasha Tasevska

Keyword(s):

Advanced Glycation End Products ◽

Healthy Adults ◽

Advanced Glycation ◽

Disease Etiology ◽

Feeding Study ◽

Fructose Intake ◽

High Fructose ◽

Significant Difference ◽

Glycation End Products ◽

End Products

Abstract Objectives Sugars form advanced glycation end products (AGEs) through natural metabolism and interactions with proteins, lipids, and nucleic acids, which accumulate in tissues and have been implicated in the etiology of chronic diseases. Due to the increased consumption of fructose and its high ability to form AGEs, a further understanding of this association is important to clarify the role of sugars in disease. Our objective was to explore the association between usual fructose intake and serum levels of AGEs in healthy adults. Methods This is a secondary analysis of a 15-d controlled feeding study (n = 100) consuming their usual diet conducted in the Phoenix metropolitan area. Participants completed two 7-d food diaries, and custom 15-d menu plans were created to replicate their habitual diet. Forty participants (mean age: 42.5y, BMI: 27.8, gender: 55% male) were selected based on their 15-d mean total fructose intake for this analysis [top and bottom 20% of the sample distribution; high fructose (HF) =20 (76.3 ± 12.5 g/day), low fructose (LF) = 20 (27.3 ± 5.4 g/day)]. Fasting serum collected five weeks after the feeding period were analyzed for carboxymethyl-lysine (CML), a major AGE, using ELISA kits. A database of 549 common foods with known CML amounts was used to calculate exogenous CML intake. A general linear model was fitted to investigate the difference in serum CML between LF and HF groups while adjusting for age, gender, BMI, and exogenous CML intake. Results Exogenous CML intake was not significantly different between the HF and LF groups (P = 0.925). Participants in the HF group had significantly higher serum CML levels compared to participants in the LF group (37.3 ± 8.4 ng/mL versus 30.5 ± 8.0 ng/mL; P = 0.013). This difference remained statistically significant after adjusting for covariates [LF vs. HF: β = −6.4 (SE = 2.9); P = 0.036; Log10(age): β = −12.0 (10.6), P = 0.267; BMI: β = 0.4 (0.4), P = 0.352), male vs. female: β = 1.2 (3.6), P = 0.753; and exogenous CML intake: β = −8.5 (10.2), P = 0.411]. Conclusions Our findings suggest that endogenous CML formation may be an explanation for the significant difference in serum CML between HF and LF groups. This is significant in further understanding mechanisms of sugar intake and disease etiology and could have implications for at-risk populations consuming a high fructose diet. Funding Sources NIH/NCI and ASU

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Presence of Glyceraldehyde-Derived Advanced Glycation End-Products in the Liver of Insulin-Resistant Mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000150 ◽

2013 ◽

Vol 83 (2) ◽

pp. 137-141 ◽

Cited By ~ 6

Author(s):

Yu Ebata ◽

Junichi Takino ◽

Hiroyuki Tsuchiya ◽

Tomohiko Sakabe ◽

Yoshito Ikeda ◽

...

Keyword(s):

Insulin Resistance ◽

Advanced Glycation End Products ◽

Protein Function ◽

Advanced Glycation ◽

Molecular Weights ◽

Insulin Resistant ◽

All Trans Retinoic Acid ◽

High Fructose ◽

Glycation End Products ◽

End Products

Insulin resistance is a fundamental feature of metabolic disorders such as metabolic syndrome. The formation of advanced glycation end-products (AGEs) is increased in patients with hyperglycemia, which results in the loss of protein function. Therefore, considerable attention has been paid to the pathological significance of AGEs in diseases associated with insulin resistance. We previously demonstrated that all-trans-retinoic acid (ATRA) ameliorated insulin resistance in mice that were fed a high-fat, high-fructose (HFHFr) diet. However, it is unclear whether the HFHFr diet increases the production of AGEs in the liver, and whether ATRA affects this production. In the present study, we investigated the production of glyceraldehyde-derived AGEs (Glycer-AGEs) in the liver of HFHFr diet-induced insulin-resistant mice using an antibody against Glycer-AGEs. We noted a remarkable formation of Glycer-AGEs with estimated molecular weights of approximately 265, 282, and 312 kDa in the liver of the insulin-resistant mice; however, the production of Glycer-AGEs was limited in the control. In accordance with previous observations, these Glycer-AGEs in mice disappeared after treatment with ATRA. These results suggest that hepatic Glycer-AGEs can be useful markers for the diagnosis and therapeutic evaluation of insulin resistance and may play a pathological role in the development of insulin resistance.

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Advanced Glycation End-Products in Common Non-Infectious Liver Diseases: Systematic Review and Meta-Analysis

Nutrients ◽

10.3390/nu13103370 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3370

Author(s):

Kamil Litwinowicz ◽

Ewa Waszczuk ◽

Andrzej Gamian

Keyword(s):

Systematic Review ◽

Liver Disease ◽

Diagnostic Accuracy ◽

Advanced Glycation End Products ◽

Meta Analysis ◽

Healthy Controls ◽

Advanced Glycation ◽

Alcoholic Fatty Liver ◽

Glycation End Products ◽

End Products

Background: Excessive intake of fructose, glucose and alcohol is associated with the development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). At the same time, these dietetic factors create an environment favorable for the generation of advanced glycation end-products. For this reason, advanced glycation end-products (AGEs) are hypothesized to play role in the development of NAFLD and ALD. In this systematic review and meta-analysis, we explore the relationship between NAFLD and ALD with AGE levels, including their diagnostic accuracy. Methods: The systematic review and meta-analysis has been pre-registered with PROSPERO (CRD42021240954) and was performed in accordance with the PRISMA guidelines. Meta-analyses were performed using the meta R package. Results: We have obtained 11 studies meeting our inclusion criteria, reporting data on 1844 participants (909 with NAFLD, 169 with ALD and 766 healthy controls). NAFLD was associated with significantly higher AGE fluorescence and serum N-(carboxyethyl)lysine (CEL) levels. Patients with alcoholic cirrhosis had significantly higher levels of N-(carboxymethyl)lysine (CML). Only individual studies examined AGEs in the context of their diagnostic accuracy. AGE fluorescence distinguished low and moderate steatosis with an AUC of 0.76. The ratio of CML, CEL and pentosidine to a soluble variant of the AGE receptor differentiated patients with NAFLD from healthy controls with high AUC (0.83–0.85). Glyceraldehyde-derived AGE separated non-alcoholic fatty liver (NAFL) from non-alcoholic steatohepatitis (NASH) with acceptable performance (AUC 0.78). Conclusions: In conclusion, NAFLD and ALD are associated with significantly higher levels of several AGEs. More research is needed to examine the diagnostic accuracy of AGEs, however individual studies show that AGEs perform well in distinguishing NAFL from NASH.

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