High dietary Fructose Drives Metabolic Dysfunction-Associated Steatotic Liver Disease via Activating ubiquitin-specific peptidase 2/11ß-hydroxysteroid dehydrogenase type 1 Pathway in Mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver-related morbidity and mortality. Though high fructose intake is acknowledged as a metabolic hazard, its role in the etiology of MASLD requires further clarification. Here, we demonstrated that high dietary fructose drives MASLD development and promotes MASLD progression in mice, and identified Usp2 as a fructose-responsive gene in the liver. Elevated USP2 levels were detected in the hepatocytes of MASLD mice; a similar increase was observed following fructose exposure in primary hepatocytes and mouse AML12 cells. Notably, hepatocytes overexpressing USP2 presented with exaggerated lipid accumulation and metabolic inflammation when exposed to fructose. Conversely, USP2 knockdown mitigated these fructose-induced changes. Furthermore, USP2 was found to activate the C/EBPα/11ß-HSD1 signaling, which further impacted the equilibrium of cortisol and cortisone in the circulation of mice. Collectively, our findings revealed the role of dietary fructose in MASLD pathogenesis and identified the USP2-mediated C/EBPα/ 11ß-HSD1 signaling as a potential target for the management of MASLD.

Promotion of lactose isomerization to fructose and lactulose in one batch by immobilized enzymes on bacterial cellulose membranes.

The production of the sugars fructose and lactulose from lactose using the enzymes ß-galactosidase and glucose isomerase immobilized on bacterial cellulose (BC) membranes has been investigated. Lactose is hydrolyzed by ß-galactosidase at 30 °C to glucose and galactose at a high conversion rate, while at the same temperature, glucose isomerase is not effective in converting the produced glucose to fructose. The rate of the isomerization reaction of glucose to fructose at 70 °C has been studied. Two types of enzyme immobilization were investigated: immobilization in one stage and immobilization in two stages. The results showed that BC membrane increased three-fold the yield and the reaction rate of fructose and lactulose production from lactose. The noteworthy enhancement of BC membranes' impact on the isomerization reaction by immobilized enzymes grants permission for a novel research avenue within the context of white biotechnology development. Additionally, this effect amplifies the role of BC in sustainability and the circular economy.

Dietary Fructose and Sodium Consumed during Early Mid-Life Are Associated with Hypertensive End-Organ Damage by Late Mid-Life in the CARDIA Cohort.

We aimed to investigate how dietary fructose and sodium impact blood pressure and risk of hypertensive target organ damage 10 years later. Data from n = 3116 individuals were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Four groups were identified based on the four possible combinations of the lower and upper 50th percentile for sodium (in mg) and fructose (expressed as percent of total daily calories). Differences among groups were ascertained and logistic regression analyses were used to assess the risk of hypertensive target organ damage (diastolic dysfunction, coronary calcification and albuminuria). Individuals in the low-fructose + low-sodium group were found to have lower SBP compared to those in the low-fructose + high-sodium and high-fructose + high-sodium groups (p < 0.05). The highest risk for hypertensive target organ damage was found for albuminuria only in the high-fructose + high-sodium group (OR = 3.328, p = 0.006) while female sex was protective across all groups against coronary calcification. Our findings highlight that sodium alone may not be the culprit for hypertension and hypertensive target organ damage, but rather when combined with an increased intake of dietary fructose, especially in middle-aged individuals.

Effect of various dietary fructose concentrations on the gallstone formation process in mice / Efecto de diversas concentraciones de fructosa dietética en el proceso de formación de cálculos biliares en ratones

Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds tobiliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consumingdiets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levelswere analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only atvery high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cho-lesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differencesin the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8)no change in biliary lipid concentrations or in micellar and vesicular phospholipids.Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructoseapparently does not alter the gallstone formation process in our experimental model.(AU)

Introducción: se dispone de escasa información sobre el efecto de la fructosa sobre los lípidos biliares. La primera etapa en la formación decálculos biliares corresponde a la cristalización del colesterol biliar, derivado de los transportadores vesiculares. El objetivo de este estudio fueinvestigar la influencia del consumo de dietas con diferentes concentraciones de fructosa en los lípidos séricos y sus implicaciones en el procesode formación de cálculos biliares.Métodos: ratones BALB/c fueron tratados con diferentes concentraciones de fructosa (10 %, 30 %, 50 % o 70 %) durante diferentes períodos(1, 2 o 5 meses). Se obtuvieron muestras de sangre, hígado y bilis. En muestras de bilis se analizaron los niveles de colesterol y fosfolípidos, ylos transportadores de colesterol (vesículas y micelas) se separaron mediante cromatografía de filtración en gel.Resultados: los animales tratados mostraron: 1) aumentos en el peso corporal similares al grupo de control; 2) aumento significativo en lostriglicéridos plasmáticos sólo a concentraciones muy altas de fructosa; 3) aumento significativo del colesterol sérico total en el tratamientodurante 1 mes; 4) ninguna variación en los niveles de HDL-colesterol; 5) aumento significativo en glucosa sérica solo a concentraciones muyaltas de fructosa; 6) ninguna diferencia en la actividad de la alanina-aminotransferasa plasmática; 7) aumento significativo en los niveles detriglicéridos hepáticos sólo a concentraciones muy altas de fructosa; 8) ningún cambio en las concentraciones de lípidos biliares o en los fos-folípidos micelares y vesiculares.Conclusión: se observaron cambios en los lípidos plasmáticos, hígado y bilis sólo en dietas con concentraciones muy altas de fructosa. Con-cluimos que la fructosa aparentemente no altera el proceso de formación de cálculos biliares en nuestro modelo experimental.(AU)

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.

Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.

High-fructose consumption suppresses insulin signaling pathway accompanied by activation of macrophage and apoptotic markers in rat testis.

Dietary high-fructose may cause metabolic disturbances; however, its effect on the reproductive system is little understood. The insulin signaling pathway is critical in testicular development, maintenance of microcirculation and spermatogenesis. Therefore, in this study, we aimed to investigate the impact of dietary high-fructose on insulin signaling pathway as well as macrophage and apoptotic markers in testicular tissue of rats. Fructose was administered to male Wistar rats as a 20% solution in drinking water for fifteen-week. Gene expression of ir-ß, irs-1, irs-2, pi3k, akt, mtor, and enos in the testicular samples was determined by real-time PCR. Protein expression of IR, IRS-1, IRS-2, PI3K, Akt, phospho-Akt (p-Akt), mTOR, eNOS, phospho-eNOS (p-eNOS), and GLUT5 was established by analysis of Western Blot. Testicular expression of occludin, CD163, CD68, caspase-8, and caspase-3 was analyzed by using immunohistochemical assay. Testicular level of fructose was measured by colorimetric method. Dietary high-fructose decreased mRNA expressions of irs-1, irs-2, pi3k, and mtor in the testicular tissue of rats. Also, this dietary intervention impaired protein expressions of IR, IRS-1, IRS-2, PI3K, p-Akt, mTOR, eNOS, and p-eNOS as well as p-Akt/Akt and p-eNOS/eNOS ratios in the testis of rats. However, a high-fructose diet increased the expression of CD163, CD68, caspase-8 and caspase-3, but decreased that of occludin, in the testicular tissue of rats. The high-fructose consumption in rats suppresses testicular insulin signaling but activates macrophages-related factors and apoptotic markers. These changes induced by dietary fructose could be related to male reproductive dysfunction.

The impact of dietary fructose on gut permeability, microbiota, abdominal adiposity, insulin signaling and reproductive function.

The excessive intake of fructose in the regular human diet could be related to global increases in metabolic disorders. Sugar-sweetened soft drinks, mostly consumed by children, adolescents, and young adults, are the main source of added fructose. Dietary high-fructose can increase intestinal permeability and circulatory endotoxin by changing the gut barrier function and microbial composition. Excess fructose transports to the liver and then triggers inflammation as well as de novo lipogenesis leading to hepatic steatosis. Fructose also induces fat deposition in adipose tissue by stimulating the expression of lipogenic genes, thus causing abdominal adiposity. Activation of the inflammatory pathway by fructose in target tissues is thought to contribute to the suppression of the insulin signaling pathway producing systemic insulin resistance. Moreover, there is some evidence that high intake of fructose negatively affects both male and female reproductive systems and may lead to infertility. This review addresses dietary high-fructose-induced deteriorations that are obvious, especially in gut permeability, microbiota, abdominal fat accumulation, insulin signaling, and reproductive function. The recognition of the detrimental effects of fructose and the development of relevant new public health policies are necessary in order to prevent diet-related metabolic disorders.

Dulaglutide mitigates high dietary fructose-induced renal fibrosis in rats through suppressing epithelial-mesenchymal transition mediated by GSK-3ß/TGF-ß1/Smad3 signaling pathways.

AIMS: High dietary fructose consumption has been linked to the development of renal fibrosis. Dulaglutide is a long acting glucagon like peptide-1 (GLP-1) analog, showing some renoprotective properties; however its action on renal fibrosis remains uncertain. We investigated the effect of dulaglutide on fructose-induced renal fibrosis in comparison to pirfenidone, as well-established anti-fibrotic drug, and the contribution of epithelial-mesenchymal transition (EMT) process and its upstream signaling. MAIN METHODS: Six week-old male Wistar albino rats received 10%w/v fructose solution in drinking water for 24 weeks and co-treated with either pirfenidone (100 mg/kg/day, orally) or dulaglutide (0.2 mg/kg/week, s.c) for the last four weeks. Lipid profile, glucose homeostasis, kidney functions were assessed. Kidneys were harvested for biochemical and histological analyses. KEY FINDINGS: High dietary fructose consumption for 24 weeks induced insulin resistance, dyslipidemia and renal dysfunction that were ameliorated by dulaglutide and pirfenidone to lesser extent. Histological examination revealed histological lesions and interstitial fibrosis in renal sections of high fructose-fed rats, which were reversed by dulaglutide or pirfenidone treatment. Both drugs modulated the EMT-related proteins by increasing the epithelial marker, E-cadherin, while suppressing the mesenchymal markers, vimentin and alpha-smooth muscle actin (α-SMA) in renal tissue. Moreover, both drugs attenuated fructose-induced upregulation of GSK-3ß/TGF-ß1/Smad3 signaling. SIGNIFICANCE: These findings suggest that dulaglutide can emerge as a promising therapeutic agent for fructose-induced renal fibrosis. These results add mechanistic insights into the anti-fibrotic action of dulaglutide through suppressing EMT and the upstream GSK-3ß/TGF-ß1/Smad3 signaling.

Dietary fructose and its association with the metabolic syndrome in Lebanese healthy adults: a cross-sectional study.

BACKGROUND: Epidemiological studies investigating the association between dietary fructose intake and the metabolic syndrome (MetS) are scarce and have produced controversial findings. This study aimed at (1) assessing total dietary fructose intake in a sample of Lebanese healthy adults, and determining the intake levels of natural vs. added fructose; (2) investigating the association of dietary fructose with MetS; and (3) identifying the socioeconomic and lifestyle factors associated with high fructose intake. METHODS: A cross-sectional survey was conducted on a representative sample of adults living in Beirut, Lebanon (n = 283). Anthropometric and biochemical data were collected, and dietary intake was assessed using a food frequency questionnaire. Intakes of naturally-occurring fructose from fructose-containing food sources, such as fruits, vegetables, honey, were considered as "natural fructose". Acknowledging that the most common form of added sugar in commodities is sucrose or High Fructose Corn Syrup (HFCS), 50% of added sugar in food products was considered as added fructose. Total dietary fructose intake was calculated by summing up natural and added fructose intakes. Logistic regression analyses were conducted to investigate the association of total, added and natural fructose intakes with the MetS and to identify the socioeconomic predictors of high fructose intake. RESULTS: Mean intake of total fructose was estimated at 51.42 ± 35.54 g/day, representing 6.58 ± 3.71% of energy intakes (EI). Natural and added fructose intakes were estimated at 12.29 ± 8.57 and 39.12 ± 34.10 g/day (1.78 ± 1.41% EI and 4.80 ± 3.56% EI), respectively. Participants in the highest quartile of total and added fructose intakes had higher odds of MetS (OR = 2.84, 95%CI: 1.01, 7.94 and OR = 3.18, 95%CI: 1.06, 9.49, respectively). In contrast, natural fructose intake was not associated with MetS. Age, gender and crowding index were identified as factors that may modulate dietary fructose intakes. CONCLUSIONS: The observed association between high added fructose intake and the MetS highlights the need for public health strategies aimed at limiting sugar intake from industrialized foods and promoting healthier dietary patterns in Lebanon.

Dietary high-fructose reduces barrier proteins and activates mitogenic signalling in the testis of a rat model: Regulatory effects of kefir supplementation.

There are limited data on the influence of fructose rich diet on the male reproductive system. Kefir may have health beneficial effects, but its mechanism of action remains mostly unclear. Herein, we investigated the impact of dietary high fructose on tight junction proteins and mitogenic pathways in rat testis as well as their modulation by kefir supplementation. Twenty-two male Wistar rats (4 weeks old) were divided into the following three groups: Control; Fructose; Fructose + Kefir. Fructose was added to drinking water at concentration of 20% and administered to the rats for 15 weeks and kefir was supplemented by gavage once a day during final 6 weeks. Dietary fructose-induced testicular degeneration was associated with the downregulation of the blood-testis barrier proteins, claudin-11 and N-cadherin as well as SIRT1 expression in testicular tissue of rats. However, p38MAPK, p-p38MAPK and p-ERK1/2 levels were increased in testis of fructose-fed rats. Interestingly, JNK1 and p-JNK1 protein levels were decreased following this dietary intervention. Raf1, ERK1/2, and caspase 3 and TUNEL staining of the testis reveal the activation of apoptosis due to fructose intake. Kefir supplementation markedly promoted the expression of claudin-11, SIRT1, JNK1 and p-JNK1 but suppressed testicular mitogenic and apoptotic factors in fructose-fed rats.

Lactobacillus plantarum improves lipogenesis and IRS-1/AKT/eNOS signalling pathway in the liver of high-fructose-fed rats.

In the present study, we investigated the influence of Lactobacillus plantarum and Lactobacillus helveticus supplementation on lipogenesis, insulin signalling and glucose transporters in liver of high-fructose-fed rats. Fructose was given to the rats as a 20% solution in drinking water for 15 weeks. Lactobacillus plantarum and L. helveticus supplementations were performed by gastric gavage once a day during final 6 weeks. Dietary high-fructose increased hepatic weight, lipid accumulation and FASN expression as well as caused a significant reduction in IRS-1 expression, pAKT/total AKT and peNOS/total eNOS ratios, but an elevation in GLUT2 and GLUT5 mRNAs in the liver. Lactobacillus plantarum supplementation decreased hepatic weight, triglyceride content and FASN expression as well as improved IRS-1/AKT/eNOS pathway and GLUT2 expression in the liver of high-fructose-fed rats. However, L. helveticus supplementation exerted a restoring effect on lipid accumulation by decreasing FASN expression, and regulating effect on IRS-1 and GLUT2 expressions.

Dietary fructose and risk of metabolic syndrome in Chinese residents aged 45 and above: results from the China National Nutrition and Health Survey.

BACKGROUND: A growing number of researches supported that dietary fructose was associated with most of the key features of metabolic syndrome (MetS). However, there was no related epidemiological studies among Chinese population, despite the sharp increase in MetS cases. This study explores the relationship between dietary fructose and MetS among Chinese residents aged 45 and above. METHODS: A total of 25,528 participants (11,574 males and 13,954 females) were included in this nationwide representative cross-sectional study of China National Nutrition and Health Survey. Dietary fructose intake was assessed by 3-day 24-h dietary records. MetS was defined by the International Diabetes Federation and Chinese Diabetes Society criteria. RESULTS: The consumption of dietary fructose was 11.6 g/day for urban residents and 7.6 g/day for rural residents. Fruits and vegetables as well as their products were the main sources of fructose intake. There was no association between dietary fructose intake and the odds of having MetS in both urban (P = 0.315) and rural residents (P = 0.230) after adjustment for confounding factors. Moreover, for urban residents participating physical activities, the odds of having MetS in the fourth quartiles (OR: 0.67; 95%CI: 0.52-0.87) was lower than that in the first quartile. In the sensitivity analysis, a significant reduction in the odds of having MetS was also found in the fourth quartiles (OR, 95%CI: 0.68, 0.51-0.90; 0.67, 0.49-0.91; 0.74, 0.56-0.99) compared with the first quartile when excluding smokers, alcohol users, and underweight/obesity, respectively. And there was no association between dietary fructose intake and the odds of having MetS after multivariate adjustment stratified by gender, smoking and alcohol use. CONCLUSIONS: Under the current dietary fructose intake status, there was no association between dietary fructose intake and the odds of having MetS among Chinese residents aged 45 and above. Physical activity and relatively low fructose intake may have a beneficial synergistic effect on MetS.

Excess dietary fructose does not alter gut microbiota or permeability in humans: A pilot randomized controlled study.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans. METHODS: We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30-40 mg/kg/m2). Each arm provided 75 grams of either fructose or glucose added to subjects' individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites. RESULTS: Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention. CONCLUSIONS: In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.

GLUT5 is a determinant of dietary fructose-mediated exacerbation of experimental colitis.

The Western diet has been suggested to contribute to the rising incidence of inflammatory bowel diseases. This has led to the hypothesis that fructose, a component of the Western diet, could play a role in the pathogenesis of inflammatory bowel diseases. A high-fructose diet is known to exacerbate experimental colitis. This study tested whether the expression of GLUT5, the fructose transporter, is a determinant of the severity of experimental colitis during elevated fructose consumption and whether ileal inflammation is associated with altered GLUT5 expression in Crohn's disease. Studies in genetically engineered mice showed that in comparison to Glut5+/+ mice, feeding a 15 kcal% fructose diet to Glut5-/- mice led to worse dextran sodium sulfate (DSS)-induced colitis. This effect was associated with elevated levels of colonic fructose and a shift in the fecal microbiota in Glut5-/- mice. Importantly, treatment with broad-spectrum antibiotics protected against the worsening of colitis mediated by dietary fructose in Glut5-/- mice. Gene expression analysis revealed that GLUT5 levels are reduced in the intestines of patients with ileal Crohn's disease. Moreover, levels of GLUT5 negatively correlated with expression of proinflammatory mediators in these samples. Collectively, these results demonstrate that dietary constituent (fructose)-host gene (GLUT5) interactions can shape the colonic microbiota, thereby impacting the severity of colitis.NEW & NOTEWORTHY This study provides the first evidence that reduced levels of GLUT5, the fructose transporter, worsen experimental colitis upon fructose feeding, an effect mediated by changes in the gut microbiota. Moreover, GLUT5 expression is reduced in Crohn's ileitis. Overall, these findings demonstrate the importance of interactions between dietary fructose and host GLUT5 as determinants of both the composition of colonic microbiota and severity of experimental colitis.

Potential mechanistic pathways underlying intestinal and hepatic effects of kefir in high-fructose-fed rats.

Excess intake of fructose may contribute to the high prevalence of metabolic disorder. In this study, we investigated the effects of kefir supplementation on the intestine-liver-adipose tissue axis in metabolic disorder induced by high-fructose diet in rats to describe mechanistic action and potential therapeutic value of kefir. Fructose was given to the rats as a 20% solution in drinking water for 15 weeks. Kefir was administrated by gastric gavage once a day during the final six weeks. Kefir supplementation improved metabolic parameters, including plasma triglyceride and insulin levels; hepatic weight, triglyceride content and fatty degeneration; omental fat mass in fructose-fed rats. Kefir supplementation decreased the ratio of Firmicutes/Bacteroidetes in feces, as well as necrotic degeneration, expression levels of nuclear factor-kappa B (NF-κB), and inducible nitric oxide synthase (iNOS), but increased expression of tight-junction proteins occludin and claudin-1, in the ileum of the fructose-fed rats. Kefir treatment also reduced the mRNA levels of key lipogenic genes sterol regulatory element-binding protein (SREBP-1c) and fatty acid synthase (FASN) together with a decline in expression of tumor necrosis factor-alpha (TNF-α), NF-κB, and glycosylated glycoprotein (CD68) in the liver. Moreover, kefir treatment improved insulin signaling at the level of insulin receptor substrate 1 (IRS-1) and phospho-endothelial nitric oxide synthase (peNOS) as well as fructose transporters (GLUT2 and GLUT5) in the liver, but not in the adipose tissue, of high-fructose-fed rats. Consequently, kefir supplementation suppresses hepatic lipogenesis and inflammatory status, but promotes insulin signaling, in association with a change of the fecal microbiota and attenuation of the intestinal permeability factors in high-fructose-fed rats. Thus, we propose that kefir has favorable effects on the hepatic and intestinal irregularities induced by fructose overconsumption.

Fructose intake is not associated to the risk of hepatic fibrosis in patients with Non-Alcoholic Fatty Liver Disease (NAFLD).

BACKGROUND & AIMS: Non-Alcoholic Fatty Liver Disease (NAFLD) has been linked to fructose intake (FI). The aim of this study was to evaluate whether the dietary FI from different food sources (added/industrial processing and natural/intrinsic to food) is associated with NAFLD and risk of hepatic fibrosis (HF). METHODS: Cross-sectional study with 128 patients with NAFLD underwent clinical, functional, laboratory, nutritional and dietary intake by 3-day-diet-record evaluation. The proportions (in grams/milliliters) of foods and beverages in the diet for each subject was computed from the database NUTTAB and classified by their processing level according to the NOVA classification to identify the source of fructose. RESULTS: The mean age was 54.0 ± 11.9 years; 72.7% were women, and BMI 32.6 ± 5.4 kg/m2. Total fructose (TF) intake was 21.6 g, natural fructose (NF) 14.8 g and added fructose (AF) 6.8 g. TF, NF, and AF intakes not differ in patients with steatosis, steatohepatitis and cirrhosis (p-values 0.140; 0.101; 0.739, respectively), and not justify HF according NAFLD score, in view of the low correlation power found (r2 0.009; 0.040; 0.051) respectively for TF, NF and AF. Patients presented elevated cardiometabolic risk due to the prevalence of 78.0% intermediate/high risk of HF; 96.8% over waist-to-height ratio (WHtR), 79.7% of metabolic syndrome (MetS), 65.6% low hand grip strength (HGS), and 70.3% had sarcopenic obesity. CONCLUSIONS: Patients had low FI compared to the amounts presented in other occidental countries and studies. No association was found between FI and NAFLD or risk of HF.

Impact of dietary propionate on fructose-induced changes in lipid metabolism, gut microbiota and short-chain fatty acids in mice.

Propionate has antimicrobial activity and is suggested to influence lipid metabolism. Here, we investigated the effect of propionate on lipid metabolism and the gut microbiome in fructose-fed mice as a model of diet-induced steatosis and gut dysbiosis. Therefore, 48 male wild-type mice were fed isoenergetic diets with either 0% fructose (F-) or 40% fructose (F+) that contained 0% propionate (P-) or 1% propionate (P+) for 7 weeks. Mice that received the F+ diets developed fatty livers, had fewer small intestinal proteobacteria and colonic actinobacteria and were characterised by changes in bacterial genera (e.g., Allobaculum, Lachnospiraceae, and Escherichia). Interestingly, mice fed the F+ diets had higher levels of propionate and butyrate in the circulation than mice fed the F- diets (p < 0.05). Treatment with propionate influenced neither hepatic or plasma lipids nor levels of circulating SCFAs. With the exception of Verrucomicrobia, other bacterial phyla were not affected by propionate.

Triose Kinase Controls the Lipogenic Potential of Fructose and Dietary Tolerance.

The surge in fructose consumption is a major factor behind the rapid rise of nonalcoholic fatty liver disease in modern society. Through flux and genetic analyses, we demonstrate that fructose is catabolized at a much higher rate than glucose, and triose kinase (TK) couples fructolysis with lipogenesis metabolically and transcriptionally. In the absence of TK, fructose oxidation is accelerated through the activation of aldehyde dehydrogenase (ALDH) and serine biosynthesis, accompanied by increased oxidative stress and fructose aversion. TK is also required by the endogenous fructolysis pathway to drive lipogenesis and hepatic triglyceride accumulation under high-fat diet and leptin-deficient conditions. Intriguingly, a nonsynonymous TK allele (rs2260655_A) segregated during human migration out of Africa behaves as TK null for its inability to rescue fructose toxicity and increase hepatic triglyceride accumulation. Therefore, we posit TK as a metabolic switch controlling the lipogenic potential of fructose and its dietary tolerance.

Effects of Lactobacillus Plantarum and Lactobacillus Helveticus on Renal Insulin Signaling, Inflammatory Markers, and Glucose Transporters in High-Fructose-Fed Rats.

Background and Objectives: The excess consumption of fructose in the diet may cause metabolic syndrome, which is associated with an increased risk of kidney disease. There is limited data on probiotic treatment in high-fructose-induced metabolic syndrome. The present study aims to investigate whether the supplementation of Lactobacillus plantarum (L. plantarum) and Lactobacillus helveticus (L. helveticus) could provide an improving effect on the renal insulin signaling effectors, inflammatory parameters, and glucose transporters in fructose-fed rats. Materials and Methods: The model of metabolic syndrome in male Wistar rats was produced by fructose, which was given as 20% solution in drinking water for 15 weeks. L. plantarum and L. helveticus supplementations were given by gastric gavage from 10 to 15 weeks of age. Results: High-fructose consumption in rats reduced renal protein expressions of insulin receptor substrate (IRS)-1, protein kinase B (AKT), and endothelial nitric oxide synthase (eNOS), which were improved by L. plantarum and partially by L. helveticus supplementations. Dietary fructose-induced elevations in renal tissue levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10, as well as expression of IL-6 mRNA, were attenuated, especially in L. plantarum treated rats. The increased renal expression of sodium-glucose cotransporter-2 (SGLT2), but not that of glucose transporter type-5 (GLUT5), was suppressed by the treatment with L. plantarum. Conclusion: Suppression in insulin signaling pathway together with the induction of inflammatory markers and upregulation of SGLT2 in fructose-fed rats were improved by L. plantarum supplementation. These findings may offer a new approach to the management of renal dysregulation induced by dietary high-fructose.

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress.

PURPOSE: High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. METHODS: In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). RESULTS: High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1ß, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser307. It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. CONCLUSION: High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.