Mutant p53 in concert with an interleukin‐27 receptor alpha deficiency causes spontaneous liver inflammation, fibrosis, and steatosis in mice

Dibra, Denada; Xia, Xueqing; Mitra, Abhisek; Cutrera, Jeffry J.; Lozano, Guillermina; Li, Shulin

doi:10.1002/hep.28379

Cited by 29 publications

(18 citation statements)

References 34 publications

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“…Recently, it has been reported that p53 play a role in not only HSCs but also in hepatocytes in the development of NASH 28 . In the present study, we used mice that were deficient in p53 in whole body, indicating that we cannot exclude the indirect influence of p53 deficiency in the other cells or tissues including hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Nishizawa

Iguchi

Fukuoka

et al. 2016

Sci Rep

113

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Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.

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Section: Discussionmentioning

confidence: 99%

IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Nishizawa

Iguchi

Fukuoka

et al. 2016

Sci Rep

113

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“… 51 In the liver, mutant p53 R172H were shown to cause spontaneous liver inflammation, steatosis, and fibrosis in vivo in combination with IL27RA deficiency. 52 However, liver-specific deletion of p53 led to the tumor formation without affecting the inflammation in the liver. 53 Some data showed that wild-type p53 accumulation in hepatocyte promote liver fibrosis by inducing the cytokine CTGF production, 54 or promote chronic inflammation by inducing HMGB1 release.…”

Section: Pathways That Trigger Nonresolving Inflammation During Hepatmentioning

confidence: 99%

Role of nonresolving inflammation in hepatocellular carcinoma development and progression

2018

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Hepatocellular carcinoma (HCC) has become a leading cause of cancer-related death, making the elucidation of its underlying mechanisms an urgent priority. Inflammation is an adaptive response to infection and tissue injury under strict regulations. When the host regulatory machine runs out of control, nonresolving inflammation occurs. Nonresolving inflammation is a recognized hallmark of cancer that substantially contributes to the development and progression of HCC. The HCC-associated inflammation can be initiated and propagated by extrinsic pathways through activation of pattern-recognition receptors (PRRs) by pathogen-associated molecule patterns (PAMPs) derived from gut microflora or damage-associated molecule patterns (DAMPs) released from dying liver cells. The inflammation can also be orchestrated by the tumor itself through secreting factors that recruit inflammatory cells to the tumor favoring the buildup of a microenvironment. Accumulating datas from human and mouse models showed that inflammation promotes HCC development by promoting proliferative and survival signaling, inducing angiogenesis, evading immune surveillance, supporting cancer stem cells, activating invasion and metastasis as well as inducing genomic instability. Targeting inflammation may represent a promising avenue for the HCC treatment. Some inhibitors targeting inflammatory pathways have been developed and under different stages of clinical trials, and one (sorafenib) have been approved by FDA. However, as most of the data were obtained from animal models, and there is a big difference between human HCC and mouse HCC models, it is challenging on successful translation from bench to bedside.

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“…However, loss of p63 in the whole animal dramatically perturbed lipid metabolism, resulting in obesity and liver damage [ 159 , 160 ] – a response at least in part due to the loss of Coiled-Coil Domain Containing 3 protein (ccdc3) expression, a secretory protein activated by p63 [ 159 ]. Finally, mice with mutations in p53 also show increased liver steatosis and fibrosis in a model of liver inflammation linked to an increased infiltration of inflammatory cells [ 161 ]. On balance, most of the studies to date suggest that p53 plays a general protective role when expressed in the liver, maintaining homeostasis and limiting the development of fatty liver disease.…”

Section: Activities Of P53 – In Vivomentioning

confidence: 99%

Control of metabolism by p53 – Cancer and beyond

Labuschagne

Zani

Vousden

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

147

120

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p53 is an important tumour suppressor gene, with loss of p53 contributing to the development of most human cancers. However, the activation of p53 in response to stress signals underpins a role for p53 in diverse aspects of health and disease. Activities of p53 that regulate metabolism can play a role in maintaining homeostasis and protecting cells from damage – so preventing disease development. By contrast, either loss or over-activation of p53 can contribute to numerous metabolic pathologies, including aging, obesity and diabetes.

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Mutant p53 in concert with an interleukin‐27 receptor alpha deficiency causes spontaneous liver inflammation, fibrosis, and steatosis in mice

Cited by 29 publications

References 34 publications

IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

Role of nonresolving inflammation in hepatocellular carcinoma development and progression

Control of metabolism by p53 – Cancer and beyond

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