The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference

Hong, Feng; Si, Chuanping; Gao, Pengfei; Cederbaum, Arthur I.; Xiong, Huabao; Lu, Yongke

doi:10.1007/s00210-015-1172-8

Cited by 25 publications

(22 citation statements)

References 35 publications

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“…This result is in contrast to many studies which reported increased levels of CYP2E1 expression in human specimens and animal models of NAFLD1214151617. This led us to assume that the presence of CYP2E1 even at basal levels might be adequate enough to induce the hepatic damaging effect through a permissive role to either upregulate other proteins or mediate their damaging effects, as reported32. Recently, following the use of high cholesterol diet (HCD), iNOS was upregulated, and was suggested as an important mediator of liver fibrosis since it was developed in WT mice, but not in iNOS -null fed HCD mice11.…”

Section: Discussioncontrasting

confidence: 74%

Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis

Abdelmegeed

Choi

Godlewski

et al. 2017

Sci Rep

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Cytochrome P450-2E1 (CYP2E1) increases oxidative stress. High hepatic cholesterol causes non-alcoholic steatohepatitis (NASH) and fibrosis. Thus, we aimed to study the role of CYP2E1 in promoting liver fibrosis by high cholesterol-containing fast-food (FF). Male wild-type (WT) and Cyp2e1-null mice were fed standard chow or FF for 2, 12, and 24 weeks. Various parameters of liver fibrosis and potential mechanisms such as oxidative and endoplasmic reticulum (ER) stress, inflammation, and insulin resistance (IR) were studied. Indirect calorimetry was also used to determine metabolic parameters. Liver histology showed that only WT fed FF (WT-FF) developed NASH and fibrosis. Hepatic levels of fibrosis protein markers were significantly increased in WT-FF. The nitroxidative stress marker iNOS, but not CYP2E1, was significantly elevated only in FF-fed WT. Serum endotoxin, TLR-4 levels, and inflammatory markers were highest in WT-FF. FAS, PPAR-α, PPAR-γ, and CB1-R were markedly altered in WT-FF. Electron microscopy and immunoblot analyses showed significantly higher levels of ER stress in FF-fed WT. Indirect calorimetry showed that Cyp2e1-null-mice fed FF exhibited consistently higher total energy expenditure (TEE) than their corresponding WT. These results demonstrate that CYP2E1 is important in fast food-mediated liver fibrosis by promoting nitroxidative and ER stress, endotoxemia, inflammation, IR, and low TEE.

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Section: Discussioncontrasting

confidence: 74%

Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis

Abdelmegeed

Choi

Godlewski

et al. 2017

Sci Rep

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“…We used our singleCellNet tool to cluster the day 4 and day 6 EB cells separately (manuscript in preparation). singleCellNet performs dimension reduction on the most variable genes by Principle Component Analysis (PCA), then uses hierarchical clustering and cutree (Becker et al, 1988), partitioning among medoids (PAM) (Kaufman and Rousseeuw, 1990), density peak finding (Rodriguez and Laio, 2014), and optionally, mclust (Scrucca et al, 2016) to assign cells to distinct clusters. singleCellNet selects the clustering that maximizes a metric of cluster quality, the average silhouette (Rousseeuw, 1987).…”

Section: Methodsmentioning

confidence: 99%

A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

Spangler

Craft

et al. 2018

Stem Cell Research

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Directed differentiation of pluripotent stem cells provides an accessible system to model development. However, the distinct cell types that emerge, their dynamics, and their relationship to progenitors in the early embryo has been difficult to decipher because of the cellular heterogeneity inherent to differentiation. Here, we used a combination of bulk RNA-Seq, single cell RNA-Seq, and bioinformatics analyses to dissect the cell types that emerge during directed differentiation of mouse embryonic stem cells as embryoid bodies and we compared them to spatially and temporally resolved transcriptional profiles of early embryos. Our single cell analyses of the day 4 embryoid bodies revealed three populations which had retained related yet distinct pluripotent signatures that resemble the pre- or post-implantation epiblast, one population of presumptive neuroectoderm, one population of mesendoderm, and four populations of neural progenitors. By day 6, the neural progenitors predominated the embryoid bodies, but both a small population of pluripotent-like cells and an anterior mesoderm-like Brachyury-expressing population were present. By comparing the day 4 and day 6 populations, we identified candidate differentiation paths, transcription factors, and signaling pathways that mark the in vitro correlate of the transition from the mid-to-late primitive streak stage.

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“…CCL4- and TAA-induced liver injuries are CYP2E1-dependent because acute liver injury induced by CCL4 or TAA was observed in WT mice but not in the cyp2e1 −/− mice [43, 44]. We treated mice with CCL4 or TAA twice a week for 1 month to induce liver fibrosis and found that CCL4 or TAA induced chronic liver injury and liver fibrosis in WT mice but not in cyp2e1 −/− mice [45]. These results indicate that CYP2E1 metabolism is indispensable for CCL4- and TAA-induced liver injury, either acute or chronic.…”

Section: Cyp2e1 and Pathogenesis Of Alcoholic Liver Diseasementioning

confidence: 99%

“…As discussed above, the Lieber-decarli ALD animal model does not induce evident liver fibrosis. We applied CCL4 and TAA models to test whether CCL4- and TAA-induced liver fibrosis may be enhanced in cyp2a5 −/− mice compared with WT mice [45]. Acute liver injury induced by one single injection of CCL4, either higher dose or lower dose, was comparable in cyp2a5 −/− mice and WT mice; chronic liver injury and liver fibrosis induced by multiple injection for one month were comparable, too.…”

Section: Cyp2a5 and Liver Fibrosismentioning

confidence: 99%

Cytochrome P450S and Alcoholic Liver Disease

Cederbaum

2018

CPD

Self Cite

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Alcohol consumption causes liver diseases, designated as Alcoholic Liver Disease (ALD). Because alcohol is detoxified by alcohol dehydrogenase (ADH), a major ethanol metabolism system, the development of ALD was initially believed to be due to malnutrition caused by alcohol metabolism in liver. The discovery of the microsomal ethanol oxidizing system (MEOS) changed this dogma. Cytochrome P450 enzymes (CYP) constitute the major components of MEOS. Cytochrome P450 2E1 (CYP2E1) in MEOS is one of the major ROS generators in liver and is considered to be contributive to ALD. Our labs have been studying the relationship between CYP2E1 and ALD for many years. Recently, we found that human CYP2A6 and its mouse analog CYP2A5 are also induced by alcohol. In mice, the alcohol induction of CYP2A5 is CYP2E1-dependent. Unlike CYP2E1, CYP2A5 protects against the development of ALD. The relationship of CYP2E1, CYP2A5, and ALD is a major focus of this review.

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The role of CYP2A5 in liver injury and fibrosis: chemical-specific difference

Cited by 25 publications

References 35 publications

Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis

Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis

A single cell transcriptional portrait of embryoid body differentiation and comparison to progenitors of the developing embryo

Cytochrome P450S and Alcoholic Liver Disease

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