Document Detail


Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.
MedLine Citation:
PMID:  23035112     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-02-28     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40732-44     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Fatty Liver / metabolism*
Fructose / metabolism
Hep G2 Cells
Humans
Lipogenesis
Mitochondria / metabolism*
Oxidative Stress*
Triglycerides / metabolism
Uric Acid / adverse effects,  metabolism*
Grant Support
ID/Acronym/Agency:
HL-68607/HL/NHLBI NIH HHS; RC4 DK090869-01/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Triglycerides; 268B43MJ25/Uric Acid; 30237-26-4/Fructose
Comments/Corrections

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