Cytidine‐5'‐Diphosphocholine Protects the Liver From Ischemia/Reperfusion Injury Preserving Mitochondrial Function and Reducing Oxidative Stress

Zazueta, Cecilia; Buelna‐Chontal, Mabel; Macías-López, Arturo; Román-Anguiano, Nadia G.; González‐Pacheco, Héctor; Pavón, Natalia; Springall, Rashidi; Aranda-Frausto, Alberto; Bojalil, Rafael; Silva-Palacios, Alejandro; Velázquez-Espejel, Rodrigo; Arzate, Sonia Galvan; Correa, Francisco

doi:10.1002/lt.25179

Cited by 31 publications

(19 citation statements)

References 38 publications

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“…The exact role each pathway contributes to the assembly and retention of hepatic TGs is not clear; however, the CDP-choline cycle is integrated into a larger metabolic network and interruption of the cycle might have a global impact on lipid-related metabolites in other pathways. CDP-choline can also protect against hypoxia and oxidative stress [82]. Thus, increased CDP-choline levels might represent a new biomarker to explain the retention of TGs in the fetal liver.…”

Section: Discussionmentioning

confidence: 99%

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates

Wesolowski¹,

Mulligan²,

Janssen³

et al. 2018

Molecular Metabolism

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) risk begins in utero in offspring of obese mothers. A critical unmet need in this field is to understand the pathways and biomarkers underlying fetal hepatic lipotoxicity and whether maternal dietary intervention during pregnancy is an effective countermeasure.MethodsWe utilized a well-established non-human primate model of chronic, maternal, Western-style diet induced obesity (OB-WSD) compared with mothers on a healthy control diet (CON) or a subset of OB-WSD mothers switched to the CON diet (diet reversal; OB-DR) prior to and for the duration of the next pregnancy. Fetuses were studied in the early 3rd trimester.ResultsFetuses from OB-WSD mothers had higher circulating triglycerides (TGs) and lower arterial oxygenation suggesting hypoxemia, compared with fetuses from CON and OB-DR mothers. Hepatic TG content, oxidative stress (TBARs), and de novo lipogenic genes were increased in fetuses from OB-WSD compared with CON mothers. Fetuses from OB-DR mothers had lower lipogenic gene expression and TBARs yet persistently higher TGs. Metabolomic profiling of fetal liver and serum (umbilical artery) revealed distinct separation of CON and OB-WSD groups, and an intermediate phenotype in fetuses from OB-DR mothers. Pathway analysis identified decreased tricarboxylic acid cycle intermediates, increased amino acid (AA) metabolism and byproducts, and increased gluconeogenesis, suggesting an increased reliance on AA metabolism to meet energy needs in the liver of fetuses from OB-WSD mothers. Components in collagen synthesis, including serum protein 5-hydroxylysine and hepatic lysine and proline, were positively correlated with hepatic TGs and TBARs, suggesting early signs of fibrosis in livers from the OB-WSD group. Importantly, hepatic gluconeogenic and arginine related intermediates and serum levels of lactate, pyruvate, several AAs, and nucleotide intermediates were normalized in the OB-DR group. However, hepatic levels of CDP-choline and total ceramide levels remained high in fetuses from OB-DR mothers.ConclusionsOur data provide new metabolic evidence that, in addition to fetal hepatic steatosis, maternal WSD creates fetal hypoxemia and increases utilization of AAs for energy production and early activation of gluconeogenic pathways in the fetal liver. When combined with hyperlipidemia and limited antioxidant activity, the fetus suffers from hepatic oxidative stress and altered intracellular metabolism which can be improved with maternal diet intervention. Our data reinforce the concept that multiple “first hits” occur in the fetus prior to development of obesity and demonstrate new biomarkers with potential clinical implications for monitoring NAFLD risk in offspring.

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Section: Discussionmentioning

confidence: 99%

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates

Wesolowski¹,

Mulligan²,

Janssen³

et al. 2018

Molecular Metabolism

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“…We also assessed the effect of miR‐449b‐5p in an in vivo rat model of hepatic I/R injury. It is well known that ALT (the specific marker for hepatic I/R injury) and AST (the nonspecific marker for hepatic injury) play important roles in hepatic I/R injury (Zazueta et al, ). In our study, both of these markers were significantly elevated in I/R rats, which is consistent with previous research (Torres‐González et al, ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐449b‐5p targets HMGB1 to attenuate hepatocyte injury in liver ischemia and reperfusion

Zhang

et al. 2019

Journal Cellular Physiology

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MicroRNAs (miRNAs) participate in the pathological process of liver ischemia/reperfusion (I/R) injury. MiR‐449b‐5p is the target miRNA of high mobility group box 1 (HMGB1). Its role and molecular mechanism in liver I/R injury remain unidentified. In this study, we found a protective effect of miR‐449b‐5p against hepatic I/R injury. HMGB1 expression significantly increased, whereas miR‐449b‐5p dramatically decreased in patients after liver transplant and in L02 cells exposed to hypoxia/reoxygenation (H/R). A dual‐luciferase reporter assay confirmed the direct interaction between miR‐449b‐5p and the 3′ untranslated region of HMGB1 messenger RNA. We also found that overexpression of miR‐449b‐5p significantly promoted cell viability and inhibited cell apoptosis of L02 cells exposed to H/R. Moreover, miR‐449b‐5p repressed HMGB1 protein expression and nuclear factor‐κB (NF‐κB) pathway activation in these L02 cells. In an in vivo rat model of hepatic I/R injury, overexpression of miR‐449b‐5p significantly decreased alanine aminotransferase and aspartate aminotransferase and inhibited the HMGB1/NF‐κB pathway. Our study thus suggests that miR‐449b‐5p alleviated hepatic I/R injury by targeting HMGB1 and deactivating the NF‐κB pathway, which may provide a novel and promising therapeutic target for hepatic I/R injury.

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“…The role of phospholipid metabolism has not been specifically investigated in hepatic IRI, but PC administration has been shown to decrease intestinal IRI (42) and brain IRI (43). While Zazueta et al found CDP-choline to ameliorate IRI in non-steatotic liver, they did not evaluate effects in steatotic liver and did not measure lipid levels (44). Given the important role of PC as the predominant phospholipid in cell membranes, the relative decrease in PCs following IRI compared to non-steatotic livers may contribute to slower resolution of and recovery from IRI in steatotic liver.…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury

Liss

Mousa

Bucha

et al. 2022

Preprint

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Liver failure secondary to nonalcoholic fatty liver disease (NAFLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of NAFLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia-reperfusion injury (IRI). There are currently no pharmacological interventions to limit hepatic IR injury because the mechanisms by which steatosis leads to increased injury are unclear. To identify potential novel mediators of IR injury, we used liquid chromatography and mass spectrometry to assess temporal changes in the hepatic lipidome in steatotic and non-steatotic livers after warm IRI in mice. Our untargeted analyses revealed distinct differences between the steatotic and non-steatotic response to IRI and highlighted dynamic changes in lipid composition with marked changes in glycerolipids and glycerophospholipids. These findings enhance our knowledge of the lipidomic changes that occur following IRI and provide a foundation for future mechanistic studies. A better understanding of the mechanisms underlying such changes will lead to novel therapeutic strategies to combat IR injury.

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Cytidine‐5'‐Diphosphocholine Protects the Liver From Ischemia/Reperfusion Injury Preserving Mitochondrial Function and Reducing Oxidative Stress

Cited by 31 publications

References 38 publications

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates

Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates

MicroRNA‐449b‐5p targets HMGB1 to attenuate hepatocyte injury in liver ischemia and reperfusion

Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury

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