title: Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver.
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.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America. miguel.lanaspagarcia@ucdenver.edu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sanchez-Lozada
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Myphuong
authors.initials: M
authors.lastname: Le
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Thomas
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.forename: Ana
authors.initials: A
authors.lastname: Andres-Hernando
authors.forename: Brandi
authors.initials: B
authors.lastname: Hunter
authors.forename: George
authors.initials: G
authors.lastname: Schreiner
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rodriguez-Iturbe
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005631:Fructokinases / Q000235:genetics / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects; D014527:Uric Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004791:Enzyme Inhibitors; C116385:MLXIPL protein, human; D014527:Uric Acid; D005632:Fructose; D000493:Allopurinol; D005631:Fructokinases