Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

Hurtado-Carneiro, Verónica; Dongil, Pilar; Pérez-García, Ana; Álvarez, Elvira; Sanz, Carmen

doi:10.3390/antiox10122028

Cited by 9 publications

(8 citation statements)

References 135 publications

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“…Alterations in hepatic glucose metabolism and mitochondrial oxidative phosphorylation are tightly interconnected with changes in redox homeostasis and signaling, and may result in decreased hepatic antioxidant defenses and increased oxidative stress [ 68 , 69 ]. Indeed, whereas the rates of aerobic metabolism and ROS production are positively correlated, the intimate liaison between redox and metabolic pathways is highlighted by their sharing of master regulators, including FoxO1 [ 33 , 40 ].…”

Section: Resultsmentioning

confidence: 99%

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

Mastrocola

Aimaretti

Alves

et al. 2022

IJMS

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KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1/FoxO1 axis is implicated in liver metabolic functions and antioxidative/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1−/−) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1−/− mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative/antiglycative functions, thus inspiring future basic and translational studies.

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Section: Resultsmentioning

confidence: 99%

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

Mastrocola

Aimaretti

Alves

et al. 2022

IJMS

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“…[16] Furthermore, oxidative damage plays a significant role in the toxic effects of PAs. [17] Oxidative stress induced by PAs metabolism further contributes to the overall toxicity associated with these compounds. Presently, 3 primary mechanisms underlie the hepatotoxicity of PAs:PAs trigger an overproduction of reactive oxygen species, inducing cellular oxidative stress.…”

Section: Mechanisms Of Hepatotoxicitymentioning

confidence: 99%

Analysis of potential risks of clinical application of Yi Dian Hong and its proprietary Chinese medicines: A review

Chen,

Mao,

Xia

et al. 2024

Medicine

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Yi Dian Hong, belonging to the Asteraceae family, finds widespread use in traditional Chinese medicine for its effectiveness in clearing heat, detoxifying, promoting blood circulation, reducing swelling, and cooling the blood. Modern medical research has revealed that Yi Dian Hong and its proprietary Chinese medicines possess biological functions such as inhibiting tumor-specific angiogenesis and regulating immune-related molecules. However, studies have identified that the primary component of Yi Dian Hong contains pyrrolizidine alkaloids (PAs), a toxic substance with potential risks to the liver, lungs, genes, and a propensity for carcinogenicity. Many countries impose strict controls on the content of PAs in herbal medicines and products. Unfortunately, China currently lacks relevant content standards, thereby introducing greater clinical application risks. To ensure the safety of clinical use of Yi Dian Hong, this review will analyze the risk associated with Yi Dian Hong and its proprietary Chinese medicines in clinical applications based on the PAs content in these medicines and provide recommendations.

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“…The protein kinase with PAS domains (PASK) is a highly conserved serine/threonine kinase containing N-terminal Per-Arnt-Sim (PAS) domains and a C-terminal kinase domain. It acts as a nutrient and energy sensor (Hurtado-Carneiro et al, 2014 and2020), and can also respond to intracellular redox state, light and oxygen (Hurtado-Carneiro et al, 2021;Dongil et al, 2018, Dongil et al, 2021. In mammals, PASK senses nutritional status and contributes to the https://doi.org/10.1017/qrd.2024.1 Published online by Cambridge University Press regulation of glucose homeostasis, energy metabolism, and oxidative stress (Hurtado-Carneiro et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“Druggability” of the PAS domains of human PASK kinase, a therapeutic target for metabolic and liver disorders

Xu,

Fan,

Zaborniak

et al. 2024

QRB Discovery

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Per-Arnt-Sim domain kinase (PASK) is a conserved metabolic sensor, which modulates the activation of critical proteins involved in liver metabolism and fitness. However, despite its key role in mastering the metabolic regulation, the molecular mechanism of PASK's activity is an ongoing research, and structural information on this important protein is scarce. To investigate this, we integrated structural bioinformatics with state-of-the-art modelling and molecular simulation techniques. Our goals were to address (1) how many regulatory PAS domains PASK is likely to have, (2) how those domains modulate the kinase activity, and (3) how those interactions could be controlled by small molecules. Our results indicated the existence of three N-terminal PAS domains. Solvent mapping and fragment docking identified a consensus set of "druggable hot-spots" within all domains, as well as at domaindomain interfaces. Those "hot-spots" could be modulated with chemically diverse small molecular probes, which may serve as a starting point for rationally-designed therapeutics modulating these specific sites. Our results identified a plausible mechanism of autoinhibition of kinase activity, suggesting that all three putative PAS domains may be required. Future work will focus on validation of the predicted PASK models, and development of small molecule inhibitors of PASK by targeting its "druggable hot-spots".

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Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

Cited by 9 publications

References 135 publications

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

Heterozygous Loss of KRIT1 in Mice Affects Metabolic Functions of the Liver, Promoting Hepatic Oxidative and Glycative Stress

Analysis of potential risks of clinical application of Yi Dian Hong and its proprietary Chinese medicines: A review

“Druggability” of the PAS domains of human PASK kinase, a therapeutic target for metabolic and liver disorders

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