Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: Potential role in fructose-dependent and -independent fatty liver

Miguel A. Lanaspa, Laura G. Sanchez-Lozada, Yea Jin Choi, Christina Cicerchi, Mehmet Kanbay, Carlos A. Roncal-Jimenez, Takuji Ishimoto, Nanxing Li, George Marek, Murat Duranay, George Schreiner, Bernardo Rodriguez-Iturbe, Takahiko Nakagawa, Duk Hee Kang, Yuri Y. Sautin, Richard J. Johnson

Research output: Contribution to journalArticlepeer-review

387 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)40732-40744
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number48
DOIs
StatePublished - 23 Nov 2012

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