title: Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.
abstract: BACKGROUND
  Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown.
  
  
  RESULTS
  Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis.
  
  
  CONCLUSIONS
  Rather than a consequence, uric acid induces fatty liver
  
  
  CONCLUSIONS
  Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO 80045, USA. 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: Yea-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kanbay
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.forename: George
authors.initials: G
authors.lastname: Marek
authors.forename: Murat
authors.initials: M
authors.lastname: Duranay
authors.forename: George
authors.initials: G
authors.lastname: Schreiner
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rodriguez-Iturbe
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D005234:Fatty Liver / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D014280:Triglycerides / Q000378:metabolism; D014527:Uric Acid / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D014280:Triglycerides; D014527:Uric Acid; D005632:Fructose