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      Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

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          Abstract

          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.

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          Most cited references 39

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          Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.

          This two-part article provides an overview of the global burden of atherothrombotic cardiovascular disease. Part I initially discusses the epidemiologic transition which has resulted in a decrease in deaths in childhood due to infections, with a concomitant increase in cardiovascular and other chronic diseases; and then provides estimates of the burden of cardiovascular (CV) diseases with specific focus on the developing countries. Next, we summarize key information on risk factors for cardiovascular disease (CVD) and indicate that their importance may have been underestimated. Then, we describe overarching factors influencing variations in CVD by ethnicity and region and the influence of urbanization. Part II of this article describes the burden of CV disease by specific region or ethnic group, the risk factors of importance, and possible strategies for prevention.
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            Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.

            Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
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              A causal role for uric acid in fructose-induced metabolic syndrome.

              The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                24 October 2012
                : 7
                : 10
                Affiliations
                [1 ]Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
                [2 ]Laboratory of Renal Physiopathology and Nephrology Department, INC Ignacio Chavez, Mexico City, Mexico
                [3 ]Cardero Therapeutics, Incorporated, Menlo Park, California, United States of America
                [4 ]Instituto Venezolano de Investigaciones Científicas-Zulia and Hospital Universitario y Universidad del Zulia, Maracaibo, Venezuela
                [5 ]Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida, Gainesville, Florida, United States of America
                Pennington Biomed Research Center, United States of America
                Author notes

                Competing Interests: The authors have read the journal’s policy and have the following conflicts: MAL, TI, and RJJ are listed as inventors on a patent application from the University of Colorado related to developing isoform-specific fructokinase inhibitors in the treatment of disorders associated with obesity and insulin resistance. Patent international number PCT/US11/46938 filed on August 8, 2011. TI and RJJ are listed as inventors on several patent applications related to lowering uric acid as a means to prevent or treat metabolic syndrome, as follows: US Patent No. 6,352,975 B1, Issued March 5, 2002 (Application No. 09/392,932, filed 09/09/1999) “Methods of Treating Hypertension and Compositions for Use Therein.” US Patent No 6,677,300. Issued Jan 13, 2004. (Application No. 09/392, 931, filed 09/09/99) “Treatment of Microvascular Angiopathies.” US Patent No. 7,030,083 B2 Issued April 18, 2006 (Application No. 10/418,529, Filed 4/16/2003) Issued Nov 10, 2005 “Treatment of eclampsia and preeclampsia.” US Patent No 7,799,794 B2, Issued Sep 21, 2010, (Application 09/892,505; Filed Jun 28, 2001 Treatment for Cardiovascular Disease. RJJ also has a patent with the University of Washington and Merck for the use of allopurinol to treat hypertension. RJJ also discloses that he has consulted for Ardea, Astellas, Danone and Novartis, that he is on the scientific board of Amway, and that he has received grants from the National Institutes of Health and from Amway, Cardero, Danone, Questcor and the Sugar Foundation. GS is employed by a commercial company (Cardero Therapeutics). There are no further patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: MAL LGSL CC TI GEG JBT CJR BRI YYS RJJ GS. Performed the experiments: MAL LGSL CC NL ML GEG CARJ CJR AAH BH. Analyzed the data: MAL CC GEG RJJ GS. Contributed reagents/materials/analysis tools: MAL RJJ. Wrote the paper: MAL RJJ.

                Article
                PONE-D-12-15109
                10.1371/journal.pone.0047948
                3480441
                23112875

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 11
                Funding
                This work was supported by Grants HL-68607 and RC4 DK090859-01, and startup funds from the University of Colorado (to RJJ) and by grant 081054 from CONACyT, Mexico (to LGSL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Energy Metabolism
                Genetics
                Genetic Mutation
                Molecular Cell Biology
                Cellular Stress Responses
                Medicine
                Anatomy and Physiology
                Gastroenterology and Hepatology
                Liver Diseases
                Nonalcoholic Steatohepatitis
                Nutrition
                Obesity

                Uncategorized

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