Excessive Fructose Intake Research Articles

A novel mechanism by which excessive fructose intake leads to hypertension

A novel mechanism by which excessive fructose intake leads to hypertension

Protective Effects of Plum on Liver and Gut Injury in Metabolic Dysfunction-Associated Fatty Liver Disease.

Metabolic dysfunction-associated fatty liver disease (MASLD), a persistent liver condition associated with metabolic syndrome, is primarily caused by excessive fructose intake and a typical Western diet. Because there is currently only one approved treatment, lifestyle and dietary interventions are crucial. This study assessed the effects of dietary intervention involving freeze-dried plum (FDP), a natural source of antioxidants containing diverse polyphenols. This study aimed to assess its potential as a protective agent against the gut-liver axis and its therapeutic effects on liver injury and gut permeability issues associated with MASLD. We indicate that 10% FDP intake restored gut barrier proteins and reduced serum endotoxin levels in the MASLD mouse models. Additionally, 10% FDP intake significantly reduced hepatic oxidative stress, lipid metabolism, and fibrosis marker levels. Interestingly, FDP intake significantly reduced the levels of inflammatory cytokine tumor necrosis factor-α and markers of liver damage, such as serum alanine aminotransferase/aspartate aminotransferase and hepatic triglycerides. These results highlight that dietary intervention with FDP that acts as a natural antioxidant may be a significant protective and therapeutic agent against liver and gut damage caused by MASLD.

Knockdown of Ketohexokinase Versus Inhibition of Its Kinase Activity Exert Divergent Effects on Fructose Metabolism.

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of MASLD. We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity to hepatocyte-specific, GalNAc-siRNA mediated knockdown of KHK in mice on a HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNAseq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis, however, via substantially different mechanisms. KHK knockdown decreased the de novo lipogenesis pathway, whereas the inhibitor increased the fatty acid oxidation pathway. Moreover, KHK knockdown completely prevented hepatic fructolysis and improved glucose tolerance. Conversely, the KHK inhibitor only partially reduced fructolysis, but it also targeted triokinase, mediating the third step of fructolysis. This leads to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. Overexpression of wild-type, but not kinase-dead KHK in cultured hepatocytes increased hepatocyte injury and glycogen accumulation when treated with fructose. The differences between KHK inhibition and knockdown are, in part, explained by the kinase-dependent and independent effects of KHK on hepatic metabolism.

Exploring fructose metabolism as a potential therapeutic approach for pancreatic cancer.

Excessive fructose intake has been associated with the development and progression of pancreatic cancer. This study aimed to elucidate the relationship between fructose utilization and pancreatic cancer progression. Our findings revealed that pancreatic cancer cells have a high capacity to utilize fructose and are capable of converting glucose to fructose via the AKR1B1-mediated polyol pathway, in addition to uptake via the fructose transporter GLUT5. Fructose metabolism exacerbates pancreatic cancer proliferation by enhancing glycolysis and accelerating the production of key metabolites that regulate angiogenesis. However, pharmacological blockade of fructose metabolism has been shown to slow pancreatic cancer progression and synergistically enhance anti-tumor capabilities when combined with anti-angiogenic agents. Overall, targeting fructose metabolism may prove to be a promising therapeutic approach in the treatment of pancreatic cancer.

Fructose shields human colorectal cancer cells from hypoxia-induced necroptosis

Recent studies have shown that high dietary fructose intake enhances intestinal tumor growth in mice. Our previous work indicated that glucose enables hypoxic colorectal cancer (CRC) cells to resist receptor-interacting protein (RIP)-dependent necroptosis. Despite having the same chemical formula, glucose and fructose are absorbed through different transporters yet both can enter the glycolytic metabolic pathway. The excessive intake of dietary fructose, leading to its overflow into the colon, allows colonic cells to absorb fructose apically. This study explores the mechanisms behind apical fructose-mediated death resistance in CRC cells under hypoxic stress. Utilizing three CRC cell lines (Caco-2, HT29, and T84) under normoxic and hypoxic conditions with varying fructose concentrations, we assessed lactate dehydrogenase (LDH) activity, RIP1/3 complex formation (a necroptosis marker), and cell integrity. We investigated the role of fructose in glycolytic-mediated death resistance using glycolytic inhibitors iodoacetate (IA, a glycolytic inhibitor to glyceraldehyde 3-phosphate dehydrogenase), and UK5099 (UK, an inhibitor to mitochondrial pyruvate carrier). Our findings reveal that apical fructose prevents the hypoxia-induced RIP-dependent necroptosis in Caco-2 and HT29 cells. Fructose exposure under hypoxia also preserved epithelial integrity. IA, but not UK, blocked fructose-mediated glycolytic metabolite production and necrosis, indicating that anaerobic glycolytic metabolites facilitate death resistance. Notably, fructose treatment upregulated pyruvate kinase (PK)-M1 mRNA in hypoxic Caco-2 and HT29 cells, while PKM2 upregulation was exclusive to HT29 cells. In conclusion, apical fructose utilization through glycolysis effectively inhibits hypoxia-induced RIP-dependent necroptosis in CRC cells, shedding light on potential metabolic adaptation mechanisms in the tumor microenvironment and suggesting novel targets for therapeutic intervention.

Loss of Nup155 promotes high fructose-driven podocyte senescence by inhibiting INO80 mRNA nuclear export

IntroductionPodocyte senescence causes podocyte loss and glomerulopathy. Excessive fructose intake is a risk factor for podocyte injury. However, whether high fructose promotes podocyte senescence remains unknown. ObjectivesTo explore the pathological mechanism by which high fructose drives podocyte senescence and find natural compounds to alleviate podocyte senescence. MethodsPodocyte senescence was characterized with senescence-associated beta-galactosidase (SA-β-gal) staining, Western blot, real-time quantitative polymerase chain reaction (qRT-PCR), comet assay and immunofluorescence. Proteomics analysis was performed to identify differentially expressed proteins in high fructose-exposed podocytes. Podocyte nuclear pore complexes (NPCs) and foot processes were observed by transmission electron microscopy. The mRNA and protein levels of nucleoporin 155 (Nup155) and inositol requiring mutant 80 (INO80) were detected by qRT-PCR, Western blot and immunofluorescence. Virtual screening was conducted to find natural compounds that target Nup155. ResultsHigh fructose increased SA-β-gal activity, protein level of p53, p21, p16 and phosphorylated histone H2AX (γ-H2AX), as well as mRNA expression of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) in rat glomeruli and podocytes. Proteomic analysis unraveled a crucial molecule Nup155, which was decreased in high fructose-induced podocyte senescence. Meanwhile, the number of podocyte NPCs was also decreased in vivo and in vitro. Consistently, high fructose suppressed nuclear export of INO80 mRNA, thereby down-regulated INO80 protein expression in podocyte senescence. Deletion of Nup155 inhibited INO80 mRNA nuclear export to induce podocyte senescence, whereas overexpression of Nup155 or INO80 alleviated high fructose-induced podocyte senescence. Ferulic acid was found to up-regulate Nup155 by both direct binding to stabilize Nup155 protein and enhancing its transcription, to promote INO80 mRNA nuclear export in the mitigation of high fructose-caused podocyte senescence. ConclusionHigh fructose induces podocyte senescence by decreasing Nup155 to inhibit INO80 mRNA nuclear export. Ferulic acid targeting Nup155 may be a potential strategy to prevent high fructose-induced podocyte senescence.

Intestinal fructose transporters GLUT5 and GLUT2 in children and adolescents with obesity and metabolic disorders

PurposeThe excessive fructose intake including high-fructose corn syrup (HFCS) may be responsible for increase of obesity occurrence. This study was designed to find potential differences in duodenal fructose transporters on mRNA and protein levels between obese and normal weight children and adolescents. Materials/methodsWe performed a cross-sectional study on a group of 106 hospitalized patients aged 12 to 18. Glucose transporter 2 (GLUT2) and glucose transporter 5 (GLUT5) mRNA as well as protein levels (ELISA and Western blot methods) were assessed in duodenal mucosa biopsies of the patients categorized as obese or normal weight. Additionally, the expression of the aforementioned transporters was analyzed in patients based on the presence of insulin resistance (IR) and metabolic syndrome (MS). ResultsIn children with obesity, increased duodenal protein levels of GLUT5 (Relative protein GLUT5 expression/ACTB) (0.027 ​± ​0.009 vs. 0.011 ​± ​0.006, p ​< ​0.05) but not GLUT2 as compared with the normal weight group, were revealed. No significant differences in duodenal relative GLUT2 and GLUT5 genes expression between the studied groups were found. There was no relationship between the presence of IR or MS and intestinal mRNA GLUT2 and GLUT5 as well as GLUT2 protein expression. ConclusionThe upregulation of the duodenal GLUT5 may contribute to obesity occurrence in children and adolescents.

Effects of different doses of glucose and fructose on central carbon metabolic pathways and intercellular wireless communication networks in humans

Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases. To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication, volunteers were given low, medium, and high doses of glucose and fructose. Serum cytokines, glucose, lactate, nicotinamide adenine dinucleotide (NADH) and metabolic enzymes were assayed, and central carbon metabolic pathway networks and cytokine communication networks were constructed. The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose. Compared with glucose, low-dose fructose decreased catabolism and increased anabolism, significantly enhanced the expression of the inflammatory cytokine interferon-γ (IFN-γ), macrophage-derived chemokine (MDC), induced protein-10 (IP-10), and eotaxin, and significantly reduced the activity of isocitrate dehydrogenase (ICDH) and pyruvate dehydrogenase complexes (PDHC). Both medium and high doses of fructose increase catabolism and anabolism, and there are more cytokines and enzymes with significant changes. Furthermore, multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways. Therefore, excessive intake of fructose should be reduced to avoid excessive inflammatory responses, allergic reactions and autoimmune diseases.

Magnoflorine Ameliorates Chronic Kidney Disease in High-Fat and High-Fructose-Fed Mice by Promoting Parkin/PINK1-Dependent Mitophagy to Inhibit NLRP3/Caspase-1-Mediated Pyroptosis.

Excessive intake of fat and fructose in Western diets has been confirmed to induce renal lipotoxicity, thereby driving the progression of chronic kidney disease (CKD). This study was conducted to evaluate the efficacy of magnoflorine in a CKD mouse model subjected to high-fat and high-fructose diets. Our results demonstrated that magnoflorine treatment ameliorated abnormal renal function indices (serum creatinine, urea nitrogen, uric acid, and urine protein) in high-fat- and high-fructose-fed mice. Histologically, renal tubular cell steatosis, lipid deposition, tubular dilatation, and glomerular fibrosis were significantly reduced by the magnoflorine treatment in these mice. Mechanistically, magnoflorine promotes Parkin/PINK1-mediated mitophagy, thereby inhibiting NLRP3/Caspase-1-mediated pyroptosis. Consistent findings were observed in the palmitic acid-incubated HK-2 cell model. Notably, both silencing of Parkin and the use of a mitophagy inhibitor reversed the inhibitory effect of magnoflorine on NLRP3 inflammasome activation in vitro. Therefore, the present study provides compelling evidence that magnoflorine improves renal injury in high-fat- and high-fructose-fed mice by promoting Parkin/PINK1-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis. Our findings suggest that dietary supplementation with magnoflorine and magnoflorine-rich foods (such as magnolia) might be an effective strategy for the prevention of CKD.

The Impact of Excessive Fructose Intake on Adipose Tissue and the Development of Childhood Obesity.

Worldwide, childhood obesity cases continue to rise, and its prevalence is known to increase the risk of non-communicable diseases typically found in adults, such as cardiovascular disease and type 2 diabetes mellitus. Thus, comprehending its multiple causes to build healthier approaches and revert this scenario is urgent. Obesity development is strongly associated with high fructose intake since the excessive consumption of this highly lipogenic sugar leads to white fat accumulation and causes white adipose tissue (WAT) inflammation, oxidative stress, and dysregulated adipokine release. Unfortunately, the global consumption of fructose has increased dramatically in recent years, which is associated with the fact that fructose is not always evident to consumers, as it is commonly added as a sweetener in food and sugar-sweetened beverages (SSB). Therefore, here, we discuss the impact of excessive fructose intake on adipose tissue biology, its contribution to childhood obesity, and current strategies for reducing high fructose and/or free sugar intake. To achieve such reductions, we conclude that it is important that the population has access to reliable information about food ingredients via food labels. Consumers also need scientific education to understand potential health risks to themselves and their children.

Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

The Effect of Exercise Intensity on Anthropometric Parameters and Renal Damage in High Fructose- Induced Mice

Excessive fructose intake disrupts carbohydrate and lipid metabolism in the kidney, resulting in kidney injury. Exercise has proven to improve the renal fatty acid metabolism, but the effect of various exercise intensities in preventing renal disorders is still unknown. The purpose of this study is to analyze the effect of various exercise intensities on anthropometric parameters and renal damage in high fructose-induced mice. The subjects were thirty-six male mice (20–30 g), aged 8 weeks were obtained and randomly assigned into 4 groups: HFr-Sed (sedentary), HFr-Ex1 (low-intensity exercise), HFr-Ex2 (moderate-intensity exercise), and HFr-Ex3 (high-intensity exercise). They were fed standard chow and high fructose solution (30%), per-oral, ad libitum for 8 weeks. The exercised groups underwent swimming, with 80% maximum duration/session, 3x/week, for 8 weeks. The result showed that there were significant differences in body weight (p &lt; 0.001), body length (p = 0.001), Lee index (p = 0.020), Body Mass Index (BMI) (p = 0.004), and serum creatinine (SCr) level (p &lt; 0.001). However, the glomerulosclerosis index and interstitial fibrosis degree were not significantly different in all groups. It can be concluded that various intensities of exercise affect the body composition and SCr level, especially moderate-intensity exercise, but do not impact the improvement of the histological kidney in high fructose-induced mice. Keyword: Exercise, healthy lifestyle, obesity, renal histology.

Impact of maternal fructose intake on liver stem/progenitor cells in offspring: Insights into developmental origins of health and disease

AimsThe developmental origin of health and disease (DOHaD) theory postulates that poor nutrition during fetal life increases the risk of disease later in life. Excessive fructose intake has been associated with obesity, diabetes, and nonalcoholic fatty liver disease, and maternal fructose intake during pregnancy has been shown to affect offspring health. In this study, we investigated the effects of high maternal fructose intake on the liver stem/progenitor cells of offspring. Main methodA fructose-based DOHaD model was established using Sprague-Dawley rats. Small hepatocytes (SHs), which play an important role in liver development and regeneration, were isolated from the offspring of dams that were fed a high-fructose corn syrup (HFCS) diet. The gene expression and DNA methylation patterns were analyzed on postnatal day (PD) 21 and 60. Key findingsMaternal HFCS intake did not affect body weight or caloric intake, but differences in gene expression and DNA methylation patterns were observed in the SHs of offspring. Functional analysis revealed an association between metabolic processes and ion transport. SignificanceThese results suggest that maternal fructose intake affects DNA methylation and gene expression in the liver stem/progenitor cells of offspring. Furthermore, the prolonged retention of these changes in gene expression and DNA methylation in adulthood (PD 60) suggests that maternal fructose intake may exert lifelong effects. These findings provide insights into the DOHaD for liver-related disorders and highlight the importance of maternal nutrition for the health of the next generation.

Excessive Glucose and Fructose Intake Aggravates the Pathogenesis of Rat Experimental Colitis

Ulcerative colitis (UC) is a relapsing and remitting disease that causes chronic inflammation and ulceration of colonic tissue, especially in the rectum region. Although sugars are rapidly digested and absorbed and can be efficiently utilized as energy in the body, they are also known to promote inflammation. Herein, we aimed to examine the effects of special diets containing excess glucose (Glu) or fructose (Fru) on the pathogenesis of dextran sulfate sodium (DSS)-induced UC in Wistar rats. The model rats (termed UC rats or UCR) were divided into three groups: DSS group, UCR fed a regular diet; DSS + Glu group, UCR fed a special diet mixed with glucose at 63% calories; DSS + Fru group, UCR fed a special diet mixed with fructose at 63% calories. The DSS + Glu and DSS + Fru groups exhibited a lower weight and colon length than the DSS group. The DSS + Fru group had a lower diet and DSS intake than the other two groups. The microscopic findings revealed that the DSS + Glu and DSS + Fru groups tended to have higher severity scores than the DSS group. The DSS + Fru group tended to have higher serum and colonic tissue concentrations of inflammatory cytokines than the DSS + Glu group. Collectively, these findings suggest that excessive glucose and fructose intake can aggravate intestinal inflammation.

Fructose-induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.

Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated AMPK-mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in PDAC patients. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC.

The chronic consumption of dietary fructose promotes the gut Clostridium species imbalance and bile acid alterations in developing nonalcoholic fatty liver disease

Excessive fructose intake is associated with the rising prevalence of nonalcoholic fatty liver disease (NAFLD). The gut microbiome (GM) and bile acids (BAs) are involved in the pathogenesis of NAFLD, but the impact of fructose on their cross-talk is unclear. In this study, adult male C57BL/6J mice were fed a normal diet with tap water (ND) or with 4% fructose in the drinking water (Fru), 60% high-fat diet with tap water (HF) or with 4% fructose solution (HFF) for 12 weeks. Targeted BA analysis was performed in five anatomical sites including the liver, ileum contents, portal serum, cecum contents, and feces. Metagenomic sequencing was performed to explore gut dysbiosis. Within 12 weeks, the 4% fructose diet could initially stimulate gut dysbiosis and BA upregulation in the ileum, portal serum, and cecum when the intestinal and hepatic transport system remained stable without hepatic lipid accumulation. However, the chronic consumption of fructose promoted HF-induced NAFLD, with significantly increased body weight, impaired glucose tolerance, and advanced liver steatosis. BA transporters were inhibited in HFF, causing the block of internal BA circulation and increased BA secretion via cecum contents and feces. Notably, lithocholic acid (LCA) and its taurine conjugates were elevated within the enterohepatic circulation. Meanwhile, the Clostridium species were significantly altered in both Fru and HFF groups and were closely associated with fructose and BA metabolism. In summary, excessive fructose caused gut dysbiosis and BA alterations, promoting HF-induced NAFLD. The crosstalk between Clostridium sp. and LCA species were potential targets in fructose-mediated NAFLD.

Effect of high-fructose consumption in pregnancy on the bone growth of offspring rats.

Growing evidence suggests that bone health is programmed in early life. Maternal diet may influence the skeletal development of offspring. We aimed to determine the possible effects of high-fructose intake during pregnancy on different aspects of long bone morphology in the offspring of rats and to initially explore the possible mechanisms. Pregnant Sprague-Dawley rats were randomly divided into four groups and intragastrically administered the same dose of distilled water (CON, n = 12), 20 g/kg/day glucose (GLU, n = 12), 10 g/kg/day fructose (LFRU, n = 12), or 20 g/kg/day fructose (HFRU, n = 12) for 21 days during gestation. Computed tomography was used to analyze the cortical and cancellous bones of the distal femur of the offspring rats, and circulating bone metabolic biomarkers were measured using enzyme immunoassay. The results showed that high-fructose intake during pregnancy could decrease body weight, impair glucose metabolism, and increase serum leptin and uric acid in offspring. The offspring in the HFRU group had higher levels of the N-terminal propeptide of type I procollagen (PINP) and the C-telopeptide of type I collagen (CTX). The bone mean density (BMD), the total cross-sectional area inside the periosteal envelope (Tt.Ar), cortical bone area (Ct.Ar), medullary (or marrow) area (Ma.Ar), and trabecular mean density of the offspring in the HFRU group were lower than those in the CON group. Tartrate-resistant acid phosphatase (Trap) staining showed that high-fructose intake during pregnancy could increase the number of osteoclasts and increase the absorption area. Our results suggested that excessive fructose intake during pregnancy could inhibit skeletal development in offspring. Thus, attention to fructose intake during pregnancy is important for bone development in offspring.

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.

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Excess fructose intake is associated with obesity, fatty liver, tooth decay, cancer, and cardiovascular diseases. Even after the ingestion of fructose, fructose concentration in the portal blood is never high; fructose is further metabolized in the liver, and the blood fructose concentration is 1/100th of the glucose concentration. It was previously thought that fructose was metabolized in the liver and not in the small intestine, but it has been reported that metabolism in the small intestine also plays an important role in fructose metabolism. Glut5 knockout mice exhibit poor fructose absorption. In addition, endogenous fructose production via the polyol pathway has also received attention; gene deletion of aldose reductase (Ar), ketohexokinase (Khk), and triokinase (Tkfc) has been found to prevent the development of fructose-induced liver lipidosis. Carbohydrate response element-binding protein (Chrebp) regulates the expression of Glut5, Khk, aldolase b, and Tkfc. We review fructose metabolism with a focus on the roles of the glucose-activating transcription factor Chrebp, fructolysis, and the polyol pathway.

Reprogramming Effects of Postbiotic Butyrate and Propionate on Maternal High-Fructose Diet-Induced Offspring Hypertension.

Maternal nutrition has a key role in the developmental programming of adult disease. Excessive maternal fructose intake contributes to offspring hypertension. Newly discovered evidence supports the idea that early-life gut microbiota are connected to hypertension later in life. Short-chain fatty acids (SCFAs), butyrate, and propionate are microbiota-derived metabolites, also known as postbiotics. The present study aimed to determine whether maternal butyrate or propionate supplementation can protect offspring from hypertension using a maternal high-fructose (HF) diet rat model. Female Sprague Dawley rats were allocated during pregnancy and lactation to (1) regular chow (ND); (2) 60% high-fructose diet (HF); (3) HF diet plus butyrate (HFB, 400 mg/kg/day); and (4) HF diet plus propionate (HFP, 200 mmol/L). Male offspring were sacrificed at 12 weeks of age. The maternal HF diet impaired the offspring's BP, which was prevented by perinatal butyrate or propionate supplementation. Both butyrate and propionate treatments similarly increased plasma concentrations of propionic acid, isobutyric acid, and valeric acid in adult offspring. Butyrate supplementation had a more profound impact on trimethylamine N-oxide metabolism and nitric oxide parameters. Whilst propionate treatment mainly influenced gut microbiota composition, it directly altered the abundance of genera Anaerovorax, Lactobacillus, Macellibacteroides, and Rothia. Our results shed new light on targeting gut microbiota through the use of postbiotics to prevent maternal HF intake-primed hypertension, a finding worthy of clinical translation.