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Roncal-Jimenez C.,University of Colorado at Denver | Lanaspa M.A.,University of Colorado at Denver | Jensen T.,University of Colorado at Denver | Sanchez-Lozada L.G.,INC Ignacio Chavez | Johnson R.J.,University of Colorado at Denver
Annals of Nutrition and Metabolism | Year: 2015

Dehydration, a condition that characterizes excessive loss of body water, is well known to be associated with acute renal dysfunction; however, it has largely been considered reversible and to be associated with no long-term effects on the kidney. Recently, an epidemic of chronic kidney disease has emerged in Central America in which the major risk factor seems to be recurrent heat-associated dehydration. This has led to studies investigating whether recurrent dehydration may lead to permanent kidney damage. Three major potential mechanisms have been identified, including the effects of vasopressin on the kidney, the activation of the aldose reductase-fructokinase pathway, and the effects of chronic hyperuricemia. The discovery of these pathways has also led to the recognition that mild dehydration may be a risk factor in progression of all types of chronic kidney diseases. Furthermore, there is some evidence that increasing hydration, particularly with water, may actually prevent CKD. Thus, a whole new area of investigation is developing that focuses on the role of water and osmolarity and their influence on kidney function and health. © 2015 S. Karger AG, Basel. Source

Sanchez-Lozada L.G.,University of Florida | Sanchez-Lozada L.G.,INC Ignacio Chavez | Sanchez-Lozada L.G.,Aurora University | Mu W.,University of Florida | And 9 more authors.
European Journal of Nutrition | Year: 2010

Background: There is evidence that disaccharide sucrose produce a greater increase in serum fructose and triglycerides (TGs) than the effect produced by their equivalent monosaccharides, suggesting that long-term exposure to sucrose or fructose + glucose could potentially result in different effects. Aim of the study: We studied the chronic effects of a combination of free fructose and glucose relative to sucrose on rat liver. Methods: Rats were fed either a combination of 30% fructose and 30% glucose (FG) or 60% sucrose (S). Control rats were fed normal rat chow (C). All rats were pair fed and were followed for 4 months. After killing, blood chemistries and liver tissue were examined. Results: Both FG-fed- and S-fed rats developed early features of metabolic syndrome when compared with C. In addition, both diets induced hepatic alterations, including variable increases in hepatic TG accumulation and fatty liver, an increase in uric acid content in the liver, as well as an increase in hepatic levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) measured in liver homogenates. Conclusions: Diets containing 30% of fructose either as free fructose and glucose, or as sucrose, induce metabolic syndrome, intrahepatic accumulation of uric acid and TGs, increased MCP-1 and TNF-α as well as fatty liver in rats. It will be relevant to determine clinically whether pharmacological reduction in uric acid levels might have a therapeutic advantage in the treatment of non-alcoholic fatty liver disease. © 2009 Springer-Verlag. Source

Solak Y.,University of Konya | Madero M.,INC Ignacio Chavez | Mcfann K.,University of Colorado at Denver | Johnson R.J.,University of Colorado at Denver
American Journal of Nephrology | Year: 2012

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular (CV) disease and is also associated with elevated uric acid, which is emerging as a nontraditional CV risk factor. We therefore evaluated uric acid as a risk factor for CV disease in subjects presenting to nephrologists with CKD who were not on medications known to alter endothelial function. Methods: 303 subjects with stage 3-5 CKD were followed for a mean of 39 months (range 6-46) and assessed for fatal and nonfatal CV events. Hyperuricemia was defined as uric acid >6.0 mg/dl for women and >7.0 mg/dl for men. In addition to other CV risk factors, endothelial function (flow-mediated dilatation), inflammatory markers (hsCRP), and insulin resistance (HOMA index and fasting insulin levels) were included in the analysis. We evaluated the association between uric acid and flow-mediated dilatation with linear regression. The impact of uric acid on composite CV events was assessed with Cox regression analysis. Results: Of a total of 303 patients, 89 had normouricemia and 214 had hyperuricemia. Both fatal (32 of 214 vs. 1 of 89 subjects) and combined fatal and nonfatal (100 of 214 vs. 13 of 89 subjects) CV events were more common in subjects with hyperuricemia compared with normal uric acid levels, and this was independent of estimated glomerular filtration rate, traditional CV risk factors including diabetes, hypertension and BMI, and nontraditional risk factors (hsCRP and endothelial function). The 46-month survival rate was 98.7% in the group with low uric acid compared to 85.8% in patients with high uric acid (p = 0.002). Conclusions: Hyperuricemia is an independent risk factor for CV events in subjects presenting with CKD who are not on medications known to alter endothelial function. © 2012 S. Karger AG, Basel. Source

Lanaspa M.A.,University of Colorado at Denver | Sanchez-Lozada L.G.,University of Colorado at Denver | Sanchez-Lozada L.G.,INC Ignacio Chavez | Cicerchi C.,University of Colorado at Denver | And 13 more authors.
PLoS ONE | Year: 2012

Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. © 2012 Lanaspa et al. Source

Ishimoto T.,University of Colorado at Denver | Lanaspa M.A.,University of Colorado at Denver | Rivard C.J.,University of Colorado at Denver | Roncal-Jimenez C.A.,University of Colorado at Denver | And 19 more authors.
Hepatology | Year: 2013

Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 weeks. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. Conclusion: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis. © 2013 by the American Association for the Study of Liver Diseases. Source

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