The role of p53 in liver fibrosis

Yu, Siyu; Ji, Guang; Zhang, Li

doi:10.3389/fphar.2022.1057829

Cited by 8 publications

(9 citation statements)

References 66 publications

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“…Therefore, the alleviating effect of 3HB on CCl 4 -induced liver fibrosis may be achieved through the restoring normal function of mouse hepatocyte mitochondria. P53 is involved and required in the anti-fibrosis process [19]. We found that 3HB also regulated the p53 signaling pathway in the liver of mice with liver fibrosis, and affected the expression of p53-related genes.…”

Section: Discussionmentioning

confidence: 89%

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Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress

Zhang,

Liu,

Wang

et al. 2024

Preprint

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3-Hydroxybutyrate (3HB) is an important metabolite and regulatory molecule produced in liver. Previous studies have shown that 3HB could be beneficial to many diseases, including brain diseases, diabetes, and most importantly, inflammation and liver related injury. Therefore, the effect of 3HB on liver fibrosis, one key step of liver diseases which proved to be reversible, is urgent to explore. In this study, the CCl4-induced mouse model of liver fibrosis has been successfully constructed and treated by 3HB. The results demonstrate that 3HB could alleviate CCl4-induced liver injury and inflammation in mice, decrease the accumulation of collagen, the expression of pro-fibrotic genes as well as inflammatory factors, and finally the degree of liver fibrosis. The transcriptome data recovers that the anti-fibrotic effect of 3HB might be exerted through several ways, such as reducing oxidative stress, improving mitochondrial function and p53 signaling pathways, proposing a safe and relatively fast possibility for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 89%

“…5C). P53 is involved and required in the anti-fibrosis process [19]. A total of 7 reported p53 regulated genes were found out from all differentially expressed genes, and 3HB treatment affected the expression of p53 controlling genes (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress

Zhang,

Liu,

Wang

et al. 2024

Preprint

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“…As the liver is a site for the elimination of toxic metabolites, the peroxisome is involved in the biosynthesis of bile acids [ 33 , 34 , 35 ]. The p53 signaling pathway is also associated with liver inflammation, fibrosis, and steatosis, and its effect on the liver changes substantially at different stages of liver injury [ 36 ]. Furthermore, several other pathways listed in Table 3 , such as tight junction and ribosome biogenesis in eukaryotes, are also reported to be associated with liver disease [ 37 , 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

Probing Liver Injuries Induced by Thioacetamide in Human In Vitro Pooled Hepatocyte Experiments

Goel,

Printz,

Pannala

et al. 2024

IJMS

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Animal studies are typically utilized to understand the complex mechanisms associated with toxicant-induced hepatotoxicity. Among the alternative approaches to animal studies, in vitro pooled human hepatocytes have the potential to capture population variability. Here, we examined the effect of the hepatotoxicant thioacetamide on pooled human hepatocytes, divided into five lots, obtained from forty diverse donors. For 24 h, pooled human hepatocytes were exposed to vehicle, 1.33 mM (low dose), and 12 mM (high dose) thioacetamide, followed by RNA-seq analysis. We assessed gene expression variability using heat maps, correlation plots, and statistical variance. We used KEGG pathways and co-expression modules to identify underlying physiological processes/pathways. The co-expression module analysis showed that the majority of the lots exhibited activation for the bile duct proliferation module. Despite lot-to-lot variability, we identified a set of common differentially expressed genes across the lots with similarities in their response to amino acid, lipid, and carbohydrate metabolism. We also examined efflux transporters and found larger lot-to-lot variability in their expression patterns, indicating a potential for alteration in toxicant bioavailability within the cells, which could in turn affect the gene expression patterns between the lots. Overall, our analysis highlights the challenges in using pooled hepatocytes to understand mechanisms of toxicity.

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“…Interestingly, our results indicate that SIRT7 deficiency increases the migration capabilities of p53-KD MEFs and alters the expression of genes related to cytoskeleton organization and cell-matrix interactions ( Figures 7D–F ). Both SIRT7 and p53 were previously associated with extracellular matrix remodeling during tissue fibrosis ( Wyman et al, 2017 ; Wu et al, 2020 ; Yu et al, 2022 ), but whether this function may be important in other situations is unknown. Because EMT is an essential process in normal embryonic development and organogenesis, our results suggest that the interplay of SIRT7 and p53 in embryonic cells may be important to sustain tissue morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

SIRT7 and p53 interaction in embryonic development and tumorigenesis

Vazquez,

Fernández-Duran,

Hernandez

et al. 2024

Front. Cell Dev. Biol.

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p53 is a hallmark tumor suppressor due in part to its role in cell cycle progression, DNA damage repair, and cellular apoptosis; its protein activity interrelates with the Sirtuin family of proteins, major regulators of the cellular response to metabolic, oxidative, and genotoxic stress. In the recent years, mammalian Sirtuin 7 (SIRT7) has emerged as a pivotal regulator of p53, fine-tuning its activity in a context dependent manner. SIRT7 is frequently overexpressed in human cancer, yet its precise role in tumorigenesis and whether it involves p53 regulation is insufficiently understood. Depletion of SIRT7 in mice results in impaired embryo development and premature aging. While p53 activity has been suggested to contribute to tissue specific dysfunction in adult Sirt7−/− mice, whether this also applies during development is currently unknown. By generating SIRT7 and p53 double-knockout mice, here we show that the demise of SIRT7-deficient embryos is not the result of p53 activity. Notably, although SIRT7 is commonly considered an oncogene, SIRT7 haploinsufficiency increases tumorigenesis in p53 knockout mice. Remarkably, in specific human tumors harboring p53 mutation, we identified that SIRT7 low expression correlates with poor patient prognosis. Transcriptomic analysis unveils a previously unrecognized interplay between SIRT7 and p53 in epithelial-to-mesenchymal transition (EMT) and extracellular matrix regulation with major implications for our understanding of embryonic development and tumor progression.

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The role of p53 in liver fibrosis

Cited by 8 publications

References 66 publications

Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress

Ketone body 3-hydroxybutyrate alleviates CCl4-induced liver fibrosis in mice through regulation of mitochondrial fission and reduction of oxidative stress

Probing Liver Injuries Induced by Thioacetamide in Human In Vitro Pooled Hepatocyte Experiments

SIRT7 and p53 interaction in embryonic development and tumorigenesis

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