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Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver
Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and that its stimulation can prevent hepatic steatosis by both enhancing f...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494720/ https://www.ncbi.nlm.nih.gov/pubmed/23152807 http://dx.doi.org/10.1371/journal.pone.0048801 |
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author | Lanaspa, Miguel A. Cicerchi, Christina Garcia, Gabriela Li, Nanxing Roncal-Jimenez, Carlos A. Rivard, Christopher J. Hunter, Brandi Andrés-Hernando, Ana Ishimoto, Takuji Sánchez-Lozada, Laura G. Thomas, Jeffrey Hodges, Robert S. Mant, Colin T. Johnson, Richard J. |
author_facet | Lanaspa, Miguel A. Cicerchi, Christina Garcia, Gabriela Li, Nanxing Roncal-Jimenez, Carlos A. Rivard, Christopher J. Hunter, Brandi Andrés-Hernando, Ana Ishimoto, Takuji Sánchez-Lozada, Laura G. Thomas, Jeffrey Hodges, Robert S. Mant, Colin T. Johnson, Richard J. |
author_sort | Lanaspa, Miguel A. |
collection | PubMed |
description | Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and that its stimulation can prevent hepatic steatosis by both enhancing fat oxidation and reducing lipogenesis. Here we show that another AMP dependent enzyme, AMPD2, has opposing effects on fatty acid oxidation when compared to AMPK. In human hepatocytres, AMPD2 activation –either by overexpression or by lowering intracellular phosphate levels with fructose- is associated with a significant reduction in AMPK activity. Likewise, silencing of AMPK spontaneously increases AMPD activity, demonstrating that these enzymes counter-regulate each other. Furthermore, we show that a downstream product of AMP metabolism through AMPD2, uric acid, can inhibit AMPK activity in human hepatocytes. Finally, we show that fructose-induced fat accumulation in hepatocytes is due to a dominant stimulation of AMPD2 despite stimulating AMPK. In this regard, AMPD2-deficient hepatocytes demonstrate a further activation of AMPK after fructose exposure in association with increased fatty acid oxidation, and conversely silencing AMPK enhances AMPD-dependent fat accumulation. In vivo, we show that sucrose fed rats also develop fatty liver that is blocked by metformin in association with both a reduction in AMPD activity and an increase in AMPK activity. In summary, AMPD and AMPK are both important in hepatic fat accumulation and counter-regulate each other. We present the novel finding that uric acid inhibits AMPK kinase activity in fructose-fed hepatocytes thus providing new insights into the pathogenesis of fatty liver. |
format | Online Article Text |
id | pubmed-3494720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34947202012-11-14 Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver Lanaspa, Miguel A. Cicerchi, Christina Garcia, Gabriela Li, Nanxing Roncal-Jimenez, Carlos A. Rivard, Christopher J. Hunter, Brandi Andrés-Hernando, Ana Ishimoto, Takuji Sánchez-Lozada, Laura G. Thomas, Jeffrey Hodges, Robert S. Mant, Colin T. Johnson, Richard J. PLoS One Research Article Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and that its stimulation can prevent hepatic steatosis by both enhancing fat oxidation and reducing lipogenesis. Here we show that another AMP dependent enzyme, AMPD2, has opposing effects on fatty acid oxidation when compared to AMPK. In human hepatocytres, AMPD2 activation –either by overexpression or by lowering intracellular phosphate levels with fructose- is associated with a significant reduction in AMPK activity. Likewise, silencing of AMPK spontaneously increases AMPD activity, demonstrating that these enzymes counter-regulate each other. Furthermore, we show that a downstream product of AMP metabolism through AMPD2, uric acid, can inhibit AMPK activity in human hepatocytes. Finally, we show that fructose-induced fat accumulation in hepatocytes is due to a dominant stimulation of AMPD2 despite stimulating AMPK. In this regard, AMPD2-deficient hepatocytes demonstrate a further activation of AMPK after fructose exposure in association with increased fatty acid oxidation, and conversely silencing AMPK enhances AMPD-dependent fat accumulation. In vivo, we show that sucrose fed rats also develop fatty liver that is blocked by metformin in association with both a reduction in AMPD activity and an increase in AMPK activity. In summary, AMPD and AMPK are both important in hepatic fat accumulation and counter-regulate each other. We present the novel finding that uric acid inhibits AMPK kinase activity in fructose-fed hepatocytes thus providing new insights into the pathogenesis of fatty liver. Public Library of Science 2012-11-09 /pmc/articles/PMC3494720/ /pubmed/23152807 http://dx.doi.org/10.1371/journal.pone.0048801 Text en © 2012 Lanaspa et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lanaspa, Miguel A. Cicerchi, Christina Garcia, Gabriela Li, Nanxing Roncal-Jimenez, Carlos A. Rivard, Christopher J. Hunter, Brandi Andrés-Hernando, Ana Ishimoto, Takuji Sánchez-Lozada, Laura G. Thomas, Jeffrey Hodges, Robert S. Mant, Colin T. Johnson, Richard J. Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title | Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title_full | Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title_fullStr | Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title_full_unstemmed | Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title_short | Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver |
title_sort | counteracting roles of amp deaminase and amp kinase in the development of fatty liver |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494720/ https://www.ncbi.nlm.nih.gov/pubmed/23152807 http://dx.doi.org/10.1371/journal.pone.0048801 |
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