Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress

By M. Lanaspa, L. Sánchez-Lozada, Yea-Jin Choi, Christina Cicerchi, M. Kanbay, Carlos Roncal-Jimenez, Takuji Ishimoto, Nanxing Li, George Marek, M. Duranay and 6 more. Journal of Biological Chemistry, 2012

663 citations recorded by the source corpus.

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. Conclusion: Rather than a consequence, uric acid induces fatty liver Significance: 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.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology, Nephrology

View Paper: https://www.semanticscholar.org/paper/146391e2852cf857bd2a626cc9d1f8b04ada2896

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Citations in the corpus

• Fructose and Sugar: A Major Mediator of Nonalcoholic Fatty Liver Disease (2018, neutral): “well as to block hepatic -fatty acid oxidation (16, 17, 63).”
• Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease (2016, background): “It has been proposed that uric acid can promote hepatic steatosis through generation of mitochondrial oxidative stress [128, 129].”