Hepatic Accumulation of Hypoxanthine: A Link Between Hyperuricemia and Nonalcoholic Fatty Liver Disease
Por:
Toledo-Ibelles, Paola, Gutierrez-Vidal, Roxana, Calixto-Tlacomulco, Sandra, Delgado-Coello, Blanca, Mas-Oliva, Jaime
Publicada:
1 oct 2021
Ahead of Print:
1 ene 2021
Categoría:
Medicine (miscellaneous)
Resumen:
Background. An elevated level of plasma uric acid has been widely
recognized as a risk factor for non-alcoholic fatty liver disease
(NAFLD), where oxidative stress and inflammation play an important role
in the pathophysiology of the disease. Although the complete molecular
mechanisms involved remain unknown, while under physiological conditions
uric acid presents antioxidant properties, hyperuricemia has been linked
to oxidative stress, chronic low-grade inflammation, and insulin
resistance, basic signs of NAFLD.
Aim of study. Employing in vivo experimentation, we aim to investigate
whether a high-fat diet rich in cholesterol (HFD), modifies the
metabolism of purines in close relationship to molecular events
associated with the development of NAFLD. In vitro experiments employing
HepG2 cells are also carried out to study the phenomenon of oxidative
stress.
Methods. Adult male rabbits were fed for 8 weeks an HFD to induce NAFLD.
At the beginning of the experiment and every 15 d until the completion
of the study, plasma levels of lipids, lipoproteins, and uric acid were
measured. Liver tissue was isolated, and histology performed followed by
the biochemical determination of hypoxanthine, protein expression of
xanthine oxidoreductase (XOR) by western blot analysis, and xanthine
oxidase (XO) activity using an enzymatic kinetic assay. Furthermore, we
employed in vitro experimentation studying HepG2 cells to measure the
effect of hypoxanthine and H2O2 upon the production of radical oxygen
species (ROS), XO activity, and cell viability.
Results and Conclusion. Hepatic tissue from rabbits fed the HFD diet
showed signs of NAFLD associated with an increased ROS concentration and
an altered purine metabolism characterized by the increase in
hypoxanthine, together with an apparent equilibrium displacement of XOR
towards the xanthine dehydrogenase (XDH) isoform of the enzyme. This
protein shift visualized by a western blot analysis, associated with an
increase in plasma uric acid and hepatocyte hypoxanthine could be
understood as a compensatory series of events secondary to the
establishment of oxidative stress associated with the chronic
establishment of fatty liver disease. (C) 2021 The Authors. Published by
Elsevier Inc. on behalf of Instituto Mexicano del Seguro Social (IMSS).
Filiaciones:
Toledo-Ibelles, Paola:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Gutierrez-Vidal, Roxana:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Calixto-Tlacomulco, Sandra:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Delgado-Coello, Blanca:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
Mas-Oliva, Jaime:
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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