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3. Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction‐associated steatotic liver disease.

Author

Núñez‐Sánchez, María Ángeles, Martínez‐Sánchez, María Antonia, Sierra‐Cruz, Marta, Lambertos, Ana, Rico‐Chazarra, Sara, Oliva‐Bolarín, Alba, Balaguer‐Román, Andrés, Yuste, José Enrique, Martínez, Carlos Manuel, Mika, Adriana, Frutos, María Dolores, Llamoza‐Torres, Camilo J, Córdoba‐Chacón, José, and Ramos‐Molina, Bruno

Subjects
ORNITHINE decarboxylase, FATTY liver, ASPARTATE aminotransferase, PALMITIC acid, PUTRESCINE, POLYAMINES, LIVER histology
Abstract

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction‐associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate‐limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet‐induced MASH mice and patients with biopsy‐proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK‐18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Antizyme Inhibitor 2-Deficient Mice Exhibit Altered Brain Polyamine Levels and Reduced Locomotor Activity

Author

Ministerio de Economía y Competitividad (España), European Commission, Fundación Séneca, Instituto de Salud Carlos III, Lambertos, Ana, Núñez-Sánchez, María Ángeles, López-García, Carlos, López-Contreras, Andrés J., Ramos-Molina, Bruno, Peñafiel, Rafael, Ministerio de Economía y Competitividad (España), European Commission, Fundación Séneca, Instituto de Salud Carlos III, Lambertos, Ana, Núñez-Sánchez, María Ángeles, López-García, Carlos, López-Contreras, Andrés J., Ramos-Molina, Bruno, and Peñafiel, Rafael

Abstract

Background: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. Methods: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. ß-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the ßGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. Results: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. Conclusions: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons.

Published
2023

12. MGRN1 as a Phenotypic Determinant of Human Melanoma Cells and a Potential Biomarker

Author

Abrisqueta, Marta, primary, Cerdido, Sonia, additional, Sánchez-Beltrán, José, additional, Martínez-Vicente, Idoya, additional, Herraiz, Cecilia, additional, Lambertos, Ana, additional, Olivares, Conchi, additional, Sevilla, Arrate, additional, Alonso, Santos, additional, Boyano, María Dolores, additional, García-Borrón, José Carlos, additional, and Jiménez-Cervantes, Celia, additional

Published
2022
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13. Antizyme Inhibitor 2-Deficient Mice Exhibit Altered Brain Polyamine Levels and Reduced Locomotor Activity.

Author

Lambertos, Ana, Nuñez-Sanchez, Maria Angeles, López-García, Carlos, López-Contreras, Andrés Joaquín, Ramos-Molina, Bruno, and Peñafiel, Rafael

Subjects
*GENE expression, *ORNITHINE decarboxylase, *ENZYME regulation, *DOPAMINERGIC neurons, *MOTOR ability, *DENDRITES
Abstract

Background: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. Methods: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. β-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the βGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. Results: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. Conclusions: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Published
2023
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20. A role for antizyme inhibitor 2 in the biosynthesis and content of histamine and serotonin in mouse mast cells

Author

Acosta-Andrade, Carlos, Lambertos, Ana, Urdiales Ruiz, José Luis, Sánchez-Jiménez, Francisca María, Peñafiel, Rafael, and Fajardo-Paredes, Ignacio José

Subjects
Antizyma, Histamina, Poliaminas, Serotonina, Mastocitos
Abstract

Polyamines (putrescine, spermidine and spermine; PAs) are required for the survival of the majority of living cells. Antizymes and antizyme inhibitors are key regulatory proteins of PA levels by affecting ornithine decarboxylase, the rate-limiting biosynthetic enzyme, and PA uptake. In addition to PA, mast cells (MC) synthesize and store in their granules the biogenically active amines histamine (Hia) and serotonin (5-HT), which are of critical importance for their function. Previously, we have performed several studies in this cell type regarding the interplay between the metabolisms of PAs and Hia and 5-HT. Our results showed that PAs affect Hia synthesis during early stages of IL-3-induced bone marrow cell differentiation into bone marrow derived MCs (BMMCs) and demonstrated that PAs are present in MC secretory granules and are important for granule homeostasis, including Hia storage and 5-HT levels. A few years ago, a novel antizyme inhibitor (AZIN2) was described. In contrast to AZIN1, AZIN2 expression is restricted to a few tissues and cell types including brain, testis and MCs. In MCs, it was recently described that AZIN2 could act as a local regulator of PA biosynthesis in association with the 5-HT granule content and release. At present, our aim is to gain further insight into the role of AZIN2 in the biosynthesis, storage and release of both Hia and 5-HT. In this study, we have generated BMMCs from both wild-type and transgenic mice with severe Azin2 hypomorphism, and have analyzed the content of PAs, Hia and 5-HT, and some elements of their metabolisms. Both PAs and 5-HT levels were reduced in Azin2 hypomorphic BMMCs compared with wild-type controls, whereas the amount of Hia was increased. Accordingly, the level of tryptophan hydroxylase 1 (the key enzyme for 5-HT biosynthesis) was reduced and the amount of enzymatic activity of histidine decarboxylase (the enzyme responsible for histamine biosynthesis) was increased in Azin2 hypomorphic BMMCs. Taken together, our results show evidence that AZIN2 has an important role in the regulation of Hia and 5-HT biosynthesis and storage in MCs.  Department of Molecular Biology and Biochemistry, and CIBER de Enfermedades Raras (CIBER-ER), Faculty of Sciences, University of Málaga, Málaga 29071, Spain. Corresponding author: I. Fajardo (ifajardo@uma.es)  This work was supported by SAF2011-26518 (MINECO, Spain) and P10-CVI-6585 and Bio-267 (Junta de Andalucia, Spain). CIBERER is an iniciative of Instituto de Salud Carlos III (Spain). Universidad de Málaga. Campus de Excelencia Internacional Andalucía-Tech. SAF2011-26518 (MINECO, Spain) and P10-CVI-6585 and Bio-267 (Junta de Andalucia, Spain. CIBERER is an iniciative of Instituto de Salud Carlos III (Spain).

Published
2015

21. A role for antizyme inhibitor 2 in the biosynthesis and content of serotonin and histamine in mouse mast cells

Author

Acosta-Andrade, Carlos, Lambertos, Ana, Urdiales-Ruiz, Jose Luis, Sanchez-Jimenez, Francisca Maria, Peñafiel, Rafael, and Fajardo-Paredes, Ignacio José

Subjects
Histamina, Poliaminas, Serotonina, Mastocitos
Abstract

Polyamines (putrescine, spermidine and spermine; PAs) are essential for the majority of living cells. Antizymes and antizyme inhibitors are key regulatory proteins of PA levels by affecting ornithine decarboxylase and PA uptake. In addition to PAs, mast cells (MC) synthesize and store in their granules histamine (Hia) and serotonin (5-HT), which are critical for their function. Our previous studies have indicated a metabolic interplay among PAs, Hia and 5-HT in this cell type. For instance, we showed that PAs affect Hia synthesis during early stages of IL-3-induced bone marrow cell differentiation into bone marrow derived MCs (BMMCs) and demonstrated that PAs are present in MC secretory granules and are important for granule homeostasis, including Hia storage and 5-HT levels. A few years ago, a novel antizyme inhibitor (AZIN2) was described whose expression is restricted to a few tissues and cell types including brain, testis and MCs. In MCs, it was recently proposed that AZIN2 could act as a local regulator of PA biosynthesis in association with 5-HT-containing granules and with 5-HT release following MC activation. To gain insight into the role of AZIN2 in the biosynthesis and storage of 5-HT and also Hia, we have generated BMMCs from both wild-type and transgenic mice with severe Azin2 hypomorphism, and have analyzed the content of PAs, 5-HT and Hia, and some elements of their metabolisms. Spermine and 5-HT levels were reduced in Azin2 hypomorphic BMMCs compared with wild-type controls, whereas the amount of Hia was increased. Accordingly, the level of tryptophan hydroxylase 1 (the key enzyme for 5-HT biosynthesis) was reduced and the amount of enzymatic activity of histidine decarboxylase (the enzyme responsible for Hia biosynthesis) was increased in Azin2 hypomorphic BMMCs. Taken together, our results show evidence that AZIN2 has an important role in the regulation of 5-HT and Hia biosynthesis and storage in MCs Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This work was supported by SAF2011-26518 (MINECO, Spain) and P10-CVI-6585 and Bio-267 (Junta de Andalucia, Spain). CIBERER is an iniciative of Instituto de Salud Carlos III (Spain).

Published
2015

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