The transcription factor zinc fingers and homeoboxes 2 alleviates NASH by transcriptional activation of phosphatase and tensin homolog

Zhao, Yichao; Gao, Liang; Jiang, Chenyan; Qin, Zihan; Zhong, Fangyuan; Yang, Yan; Tong, Renyang; Zhou, Meng; Yuan, Ancai; Pu, Jun

doi:10.1002/hep.32165

Cited by 15 publications

(25 citation statements)

References 53 publications

(68 reference statements)

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“…ZHX2 (zinc fingers and homeoboxes 2) is the transcription factor that promotes the transcription of phosphatase and tensin homolog (PTEN) and alleviates NASH (advanced liver diseases) [ 96 ]. GPCRs, PI3K, and Rho signaling pathways regulate the cascades of TAU and Aβ in AD ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

1-L Transcription in Alzheimer’s Disease

Nahálka

2022

CIMB

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Alzheimer’s disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer’s disease is presented here, the β-amyloid peptide is considered an important RNA recognition/binding peptide. 1-L transcription revealed compatible sequences with AAUAAA (PAS signal) and UUUC (class III ARE rich in U) in the Aβ peptide, supporting the peptide–RNA regulatory model. When a hypothetical model of fibril selection with the prionic character of amyloid assemblies is added to the peptide-RNA regulatory model, the downregulation of the PI3K-Akt pathway and the upregulation of the PLC-IP3 pathway are well explained. The model explains why neurons are less protected from inflammation and why microglia are activated; why mitochondria are destabilized; why the autophagic flux is destabilized; and why the post-transcriptional attenuation of the axonal signal “noise” is interrupted. For example, the model suggests that Aβ peptide may post-transcriptionally control ELAVL2 (ELAV-like RNA binding protein 2) and DCP2 (decapping mRNA protein 2), which are known to regulate RNA processing, transport, and stability.

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Section: Resultsmentioning

confidence: 99%

1-L Transcription in Alzheimer’s Disease

Nahálka

2022

CIMB

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“…Mice in this study did not develop tumors, so we cannot compare this model with our DEN model regarding HCC formation. However, it should be noted that Zhao et al (41) and Yue et al (21) focused on hepatocytes, although it is increasing clear that NPCs also play critical roles in NAFLD progression from simple steatosis to NASH, cirrhosis and HCC (42). DEN-induced HCC depends on an inflammatory response and IL-6 production in activated Kupffer cells (29, 33).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Zhao et al showed that Zhx2 alleviates NASH through PTEN activation (41). This study utilized a high-fat high-cholesterol diet to induce NASH and used both liver-specific Zhx2 knock-out and liver-specific Zhx2 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Zinc Fingers and Homeoboxes 2 is Required for Diethylnitrosamine-induced Liver Tumor Formation in C57BL/6 Mice

Jiang

Turpin

Qiu

et al. 2022

Preprint

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Liver cancer, comprised mainly of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor Zinc Fingers and Homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2-deficient mice using the Diethylnitrosamine (DEN)-induced liver tumor model. Our study using whole-body Zhx2 knock-out (Zhx2KO) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure. Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme CYP2E1 and DNA polymerase delta 2, or in the numbers of γH2AX foci between Zhx2KO and wild-type (Zhx2wt) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2KO livers showed fewer positive foci for Ki67 staining and reduced IL-6 and AKT2 expression compared to Zhx2wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN-treated liver-specific Zhx2 knock-out mice, suggesting that Zhx2 acts in both hepatocytes and non-parenchymal cells to inhibit tumor formation. Analysis of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 mRNA and protein levels were significantly higher in HCC patients and associated with clinical pathological parameters. Conclusions: In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in HCC patients.

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“…In a recent study, it has been shown that the transcription factor zinc fingers and homeoboxes 2 (ZHX2) also has a role in NASH models [ 67 ]. ZHX2 suppressed NASH progression in steatotic hepatic cells and downgraded inflammation and fibrosis in liver.…”

Section: Genomic Approaches For Defatting Strategiesmentioning

confidence: 99%

A Review of Defatting Strategies for Non-Alcoholic Fatty Liver Disease

Young

Doğan

Watkins

et al. 2022

IJMS

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Non-alcoholic fatty liver disease is a huge cause of chronic liver failure around the world. This condition has become more prevalent as rates of metabolic syndrome, type 2 diabetes, and obesity have also escalated. The unfortunate outcome for many people is liver cirrhosis that warrants transplantation or being unable to receive a transplant since many livers are discarded due to high levels of steatosis. Over the past several years, however, a great deal of work has gone into understanding the pathophysiology of this disease as well as possible treatment options. This review summarizes various defatting strategies including in vitro use of pharmacologic agents, machine perfusion of extracted livers, and genomic approaches targeting specific proteins. The goal of the field is to reduce the number of necessary transplants and expand the pool of organs available for use.

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The transcription factor zinc fingers and homeoboxes 2 alleviates NASH by transcriptional activation of phosphatase and tensin homolog

Cited by 15 publications

References 53 publications

1-L Transcription in Alzheimer’s Disease

1-L Transcription in Alzheimer’s Disease

Zinc Fingers and Homeoboxes 2 is Required for Diethylnitrosamine-induced Liver Tumor Formation in C57BL/6 Mice

A Review of Defatting Strategies for Non-Alcoholic Fatty Liver Disease

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