PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation

Tobón-Cornejo, Sandra; Vargas‐Castillo, Ariana; Leyva-Martínez, Alekxa; Ortíz, Víctor; Noriega, Lilia G.; Velázquez-Villegas, Laura A.; Alemán, Gabriela; Furosawa-Carballeda, Janette; Torres, Nimbe; Tovar, Armando R.

doi:10.1016/j.metabol.2021.154705

Cited by 8 publications

(4 citation statements)

References 36 publications

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“…The latter, furthermore, coincides with a consistently measured decrease (in lipidomics studies) of DG, as previously reported (Yang et al, 2023), which—in contrast to the reported increase of DG in zebrafish embryos exposed to PFOA (Yang et al, 2023)—points to a possible PFOS‐specific role of inter‐related pathways of fatty acids (i.e., β‐oxidation) and glycerolipid metabolism. In addition, although both levels of Phe and Trp were conspicuously found to significantly decrease in PFOS‐exposed embryos, all three aromatic amino acids (i.e., Phe, Tyr, and Trp) were significantly increased in PFOA‐exposed embryos: aligned with this finding, it has been shown in several studies that, aligned with this observation, PPARα downregulates amino acid catabolism (Contreras et al, 2015; Kersten et al, 2001; Tobón‐Cornejo et al, 2021).…”

Section: Resultsmentioning

confidence: 59%

An Integrated Metabolomics‐Based Model, and Identification of Potential Biomarkers, of Perfluorooctane Sulfonic Acid Toxicity in Zebrafish Embryos

Annunziato,

Bashirova,

Eeza

et al. 2024

Enviro Toxic and Chemistry

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Known for their high stability and surfactant properties, per‐ and polyfluoroalkyl substances (PFAS) have been widely used in a range of manufactured products. Despite being largely phased out due to concerns regarding their persistence, bioaccumulation, and toxicity, legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid continue to persist at high levels in the environment, posing risks to aquatic organisms. We used high‐resolution magic angle spinning nuclear magnetic resonance spectroscopy in intact zebrafish (Danio rerio) embryos to investigate the metabolic pathways altered by PFOS both before and after hatching (i.e., 24 and 72 h post fertilization [hpf], respectively). Assessment of embryotoxicity found embryo lethality in the parts‐per‐million range with no significant difference in mortality between the 24‐ and 72‐hpf exposure groups. Metabolic profiling revealed mostly consistent changes between the two exposure groups, with altered metabolites generally associated with oxidative stress, lipid metabolism, energy production, and mitochondrial function, as well as specific targeting of the liver and central nervous system as key systems. These metabolic changes were further supported by analyses of tissue‐specific production of reactive oxygen species, as well as nontargeted mass spectrometric lipid profiling. Our findings suggest that PFOS‐induced metabolic changes in zebrafish embryos may be mediated through previously described interactions with regulatory and transcription factors leading to disruption of mitochondrial function and energy metabolism. The present study proposes a systems‐level model of PFOS toxicity in early life stages of zebrafish, and also identifies potential biomarkers of effect and exposure for improved environmental biomonitoring. Environ Toxicol Chem 2024;00:1–19. © 2024 SETAC

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Section: Resultsmentioning

confidence: 59%

An Integrated Metabolomics‐Based Model, and Identification of Potential Biomarkers, of Perfluorooctane Sulfonic Acid Toxicity in Zebrafish Embryos

Annunziato,

Bashirova,

Eeza

et al. 2024

Enviro Toxic and Chemistry

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“…Although a high-protein food preference of patients with citrin deficiency could induce elevated levels of BUN elevation, this would not be a primary cause during the early postnatal period as babies cannot spontaneously choose a high-protein formula. Peroxisome proliferator-activated receptor alpha (PPARα), which may be associated with the pathophysiology of citrin deficiency [20] , could induce protein catabolism. Pparα knockout mice showed elevated levels of BUN, which is consistent with the phenomenon in citrin deficiency [21] .…”

Section: Discussionmentioning

confidence: 99%

Usefulness of serum BUN or BUN/creatinine ratio as markers for citrin deficiency in positive cases of newborn screening

Suzuki

Wada

Mikami-Saito

et al. 2022

Molecular Genetics and Metabolism Reports

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“…Analysis of other AADE such as glutaminase 2 or tyrosine aminotransferase gene promoters, also provides evidence of the presence of response elements for CRE, HNF1, HNF-5, and GRE [64,65]. Interestingly, PPARα is known to promote proteasomal degradation of HNF4α, decreasing the transcription of AADE, but at the same time promoting the expression of fatty acid oxidation enzymes, resulting in a switch-off mechanism to prevent amino acid oxidation but activating the utilization of fatty acids as an energy source [63]. In addition, other conditions can induce the expression of specific AADEs.…”

Section: Transcriptional Regulation Of Amino Acid Degrading Enzymesmentioning

confidence: 98%

“…In addition, stimulation with phorbol 12-myristate, 13-acetate (PMA) also activates the HAL promoter, indicating that gene expression of this catabolizing enzyme gene can also be stimulated via PKC [61]. Recently, HNF4α has been found to regulate the GLS2 promoter positively, and the response elements for HNF4 are conserved between human, mouse, and rabbit [62], response element also found in the SDS and HAL promoters [59,63]. Analysis of other AADE such as glutaminase 2 or tyrosine aminotransferase gene promoters, also provides evidence of the presence of response elements for CRE, HNF1, HNF-5, and GRE [64,65].…”

Section: Transcriptional Regulation Of Amino Acid Degrading Enzymesmentioning

confidence: 99%

Amino Acid Catabolism: An Overlooked Area of Metabolism

Torres,

Tobón-Cornejo,

Velazquez-Villegas

et al. 2023

Nutrients

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Amino acids have been extensively studied in nutrition, mainly as key elements for maintaining optimal protein synthesis in the body as well as precursors of various nitrogen-containing compounds. However, it is now known that amino acid catabolism is an important element for the metabolic control of different biological processes, although it is still a developing field to have a deeper understanding of its biological implications. The mechanisms involved in the regulation of amino acid catabolism now include the contribution of the gut microbiota to amino acid oxidation and metabolite generation in the intestine, the molecular mechanisms of transcriptional control, and the participation of specific miRNAs involved in the regulation of amino acid degrading enzymes. In addition, molecules derived from amino acid catabolism play a role in metabolism as they are used in the epigenetic regulation of many genes. Thus, this review aims to examine the mechanisms of amino acid catabolism and to support the idea that this process is associated with the immune response, abnormalities during obesity, in particular insulin resistance, and the regulation of thermogenesis.

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PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation

Cited by 8 publications

References 36 publications

An Integrated Metabolomics‐Based Model, and Identification of Potential Biomarkers, of Perfluorooctane Sulfonic Acid Toxicity in Zebrafish Embryos

An Integrated Metabolomics‐Based Model, and Identification of Potential Biomarkers, of Perfluorooctane Sulfonic Acid Toxicity in Zebrafish Embryos

Usefulness of serum BUN or BUN/creatinine ratio as markers for citrin deficiency in positive cases of newborn screening

Amino Acid Catabolism: An Overlooked Area of Metabolism

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