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

• Published in: PloS one Vol. 7; no. 10; p. e47948
• Main Authors: Lanaspa, Miguel A., Sanchez-Lozada, Laura G., Cicerchi, Christina, Li, Nanxing, Roncal-Jimenez, Carlos A., Ishimoto, Takuji, Le, Myphuong, Garcia, Gabriela E., Thomas, Jeffrey B., Rivard, Christopher J., Andres-Hernando, Ana, Hunter, Brandi, Schreiner, George, Rodriguez-Iturbe, Bernardo, Sautin, Yuri Y., Johnson, Richard J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.10.2012; Public Library of Science (PLoS)
• Subjects: Acid production; Acids; Allopurinol - pharmacology; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biology; Diabetes; Diabetes mellitus; Diet; Dietary intake; Enzyme Inhibitors - pharmacology; Epidemics; Experiments; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Fructokinase; Fructokinases - genetics; Fructokinases - metabolism; Fructose; Fructose - metabolism; Glucose; Hep G2 Cells; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Insulin; Insulin resistance; Kidney diseases; Kinases; Laboratory animals; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Male; Medicine; Metabolic disorders; Metabolic syndrome; Metabolism; Nephrology; Obesity; Oxidative stress; Phosphates; Physiological aspects; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Sensitizing; Transcription activation; Transcriptional Activation; Triglycerides; Type 2 diabetes; Up-Regulation - drug effects; Uric acid; Uric Acid - antagonists & inhibitors; Uric Acid - metabolism; United States > US; Colorado
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047948

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.