Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats

Fan, Ting; Hu, Ping; Wang, Jian; Wei, Ji; Zhang, Qing; Ning, Bei Fang; Yin, Chuan; Zhang, Xin; Xie, Wei; Chen, Yue Xiang; Shi, Bin

doi:10.1111/1751-2980.12042

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…In support of this possibility are the previously alluded studies showing how adenoviral gene transfer of HNF1a and HNF4a in rodent models partially restored liver-specific gene expression, hepatocellular function and even attenuated fibrosis and HCC development [178][179][180]188]. Moreover, delivery of HNF4a to rats with established cirrhosis also resulted in the reversal of fibrosis and the restoration of some functional parameters [203]. Nevertheless, this beneficial effect was only fully observed in animals at early stages of fibrosis and not in those with advanced disease [203].…”

Section: Translational Perspectivesmentioning

confidence: 79%

“…Moreover, delivery of HNF4a to rats with established cirrhosis also resulted in the reversal of fibrosis and the restoration of some functional parameters [203]. Nevertheless, this beneficial effect was only fully observed in animals at early stages of fibrosis and not in those with advanced disease [203]. Such difference may be attributed to the difficulty of resolving thick and cross-linked fibrous septa found in progressed cirrhosis [204].…”

Section: Translational Perspectivesmentioning

confidence: 99%

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Regulation of hepatocyte identity and quiescence

Berasain

Avila

2015

Cell. Mol. Life Sci.

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The liver is a highly differentiated organ with a central role in metabolism, detoxification and systemic homeostasis. To perform its multiple tasks, liver parenchymal cells, the hepatocytes, express a large complement of enabling genes defining their complex phenotype. This phenotype is progressively acquired during fetal development and needs to be maintained in adulthood to guarantee the individual's survival. Upon injury or loss of functional mass, the liver displays an extraordinary regenerative response, mainly based on the proliferation of hepatocytes which otherwise are long-lived quiescent cells. Increasing observations suggest that loss of hepatocellular differentiation and quiescence underlie liver malfunction in chronic liver disease and pave the way for hepatocellular carcinoma development. Here, we briefly review the essential mechanisms leading to the acquisition of liver maturity. We also identify the key molecular factors involved in the preservation of hepatocellular homeostasis and finally discuss potential strategies to preserve liver identity and function.

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Section: Translational Perspectivesmentioning

confidence: 79%

Section: Translational Perspectivesmentioning

confidence: 99%

Regulation of hepatocyte identity and quiescence

Berasain

Avila

2015

Cell. Mol. Life Sci.

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“…Xie et al have provided evidence that forced expression of HNF4α can alleviate hepatic fibrosis and cirrhosis and block HCC development (37, 64, 65). Further work on how HNF4α is regulated and targets genes for activation or inhibition will be needed in order to selectively target genes in a given disease state.…”

Section: Hnf4α and Proliferationmentioning

confidence: 99%

Role of Hepatocyte Nuclear Factor 4α (HNF4α) in Cell Proliferation and Cancer

Walesky

Apte²

2015

gene expr

130

118

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Hepatocyte nuclear factor 4 alpha (HNF4α) is an orphan nuclear receptor commonly known as the master regulator of hepatic differentiation owing to the large number of hepatocyte-specific genes it regulates. Whereas the role of HNF4α in hepatocyte differentiation is well recognized and extensively studied, its role in regulation of cell proliferation is relatively less known. Recent studies have revealed that HNF4α inhibits proliferation not only of hepatocytes but also cells in colon and kidney. Further, a growing number of studies have demonstrated that inhibition or loss of HNF4α promotes tumorigenesis in the liver and colon, and re-expression of HNF4α results in decreased cancer growth. Studies using tissue-specific conditional knockout mice, knock-in studies, and combinatorial bioinformatics of RNA/ChIP-sequencing data indicate that the mechanisms of HNF4α-mediated inhibition of cell proliferation are multifold involving epigenetic repression of pro-mitogenic genes, significant crosstalk with other cell cycle regulators including c-Myc and Cyclin D1, and regulation of miRNAs. Furthermore, studies indicate that post-translational modifications of HNF4α may change its activity and may be at the core of its dual role as a differentiation factor and repressor of proliferation. This review summarizes recent findings on the role of HNF4α in cell proliferation and highlights the newly understood function of this old receptor.

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“…Furthermore, HNF4α introduction blocks the development of HCC by inhibiting CSCs generation in rats . Interestingly, HNF4α overexpression also significantly attenuates liver fibrosis and reverses early cirrhosis . Considering that most HCC occurs in cirrhotic liver, the dual therapeutic effect of HNF4α on liver fibrosis and cancer shows its great potential in the treatment of HCC.…”

Section: Existing Strategies Of Differentiation Therapy For Solid Tumorsmentioning

confidence: 99%

“…In viral vectors, adenoviral vector has been reported to be more efficient than non-viral gene transfer methods, and to be stable in vivo and relatively safe because it rarely causes any significant disease. 29 In our previous studies [22][23][24][25][26][27][28] we have also successfully used a vector based upon replication-deficient E1 and E3 adenovirus to express HNFs with low toxicity both in vivo and in vitro, indicating that adenovirus can be designed as a useful instrument for gene therapy. Adeno-associated virus (AAV) is another viral vector that has been widely studied for gene replacement therapy of cancers over the past few years and is currently undergoing clinical trials.…”

Section: Transcription Factor-based Strategymentioning

confidence: 99%

Differentiation therapy for solid tumors

Zhang

Xie

2014

J of Digest Diseases

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Differentiation therapy for tumors refers to treating malignant tumors via the induction of cell differentiation. The best characterized clinical application of differentiation therapy is the use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia (APL), which markedly improved the outcome of this disease. Unlike the situation with APL, the development of differentiation therapy for solid tumors is far from satisfactory. To date, no differentiation-inducing agents have been demonstrated to exert a curative effect on solid tumors. However, over the past decade progress in understanding the differentiation pathways and the development of differentiation-inducing agents might shed new light on the differentiation therapy for solid tumors.

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Regression effect of hepatocyte nuclear factor 4α on liver cirrhosis in rats

Abstract: Our findings broaden the knowledge on the reversibility of different stages of cirrhosis as HNF4α could present a promising alternative for the treatment of liver cirrhosis.

Cited by 10 publications

References 45 publications

Regulation of hepatocyte identity and quiescence

Regulation of hepatocyte identity and quiescence

Role of Hepatocyte Nuclear Factor 4α (HNF4α) in Cell Proliferation and Cancer

Differentiation therapy for solid tumors

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