p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice

Tomita, Kengo; Teratani, Toshiaki; Suzuki, Takahiro; Oshikawa, Tetsuya; Yokoyama, Hirokazu; Shimamura, Katsuyoshi; Nishiyama, Kiyoshi; Mataki, Norikazu; Irie, Rie; Minamino, Tohru; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Saito, Hidetsugu; Shimizu, Ippei; Yoshida, Yohko; Hokari, Ryota; Sugiyama, Kazuo; Hatsuse, Kazuo; Yamamoto, Junji; Kanai, Takanori; Miura, Soichiro; Hibi, Toshifumi

doi:10.1016/j.jhep.2012.05.013

Cited by 103 publications

(118 citation statements)

References 28 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…These data indicate a likely role for hepatocyte senescence in stellate cell activation and fibrosis progression. This is further corroborated in a study of p53-decifient mice with nutrition-directed steatohepatitis, which demonstrated reduced hepatocyte p21 expression and reduced hepatic stellate cell activation (reduced α-SMA and collagen expression) compared to the wild type counterpart [66]. However, experimental evidence for such direct causal link between hepatocyte senescence and stellate cell activation (and therefore fibrosis) is lacking in man.…”

Section: Cellular Senescence and Liver Fibrosismentioning

confidence: 63%

Senescence in chronic liver disease: Is the future in aging?

Aravinthan

Alexander

2016

Journal of Hepatology

132

116

View full text Add to dashboard Cite

Cellular senescence is a fundamental, complex mechanism with an important protective role present from embryogenesis to late life across all species. It limits the proliferative potential of damaged cells thus protecting against malignant change, but at the expense of substantial alterations to the microenvironment and tissue homeostasis, driving inflammation, fibrosis and paradoxically, malignant disease if the process is sustained. Cellular senescence has attracted considerable recent interest with recognition of pathways linking aging, malignancy and insulin resistance and the current focus on therapeutic interventions to extend health-span. There are major implications for hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells and immune cells has been implicated in chronic liver disease progression. This review focuses on cellular senescence in chronic liver disease and explores therapeutic opportunities.

show abstract

Section: Cellular Senescence and Liver Fibrosismentioning

confidence: 63%

Senescence in chronic liver disease: Is the future in aging?

Aravinthan

Alexander

2016

Journal of Hepatology

132

116

View full text Add to dashboard Cite

show abstract

“…4,6,11 A positive paracrine effect from senescent hepatocytes on hepatic stellate cell activation is one explanation for this association and is consistent with a recent study. 36 However, stellate cell senescence leads to reduced liver fibrosis, 9 as senescent cells lose their function specific to that cell type during senescence. 37 A p21 SNP variant that leads to increased p21 expression is likely to cause increased hepatocyte p21 expression and activation of stellate cells to cause liver fibrosis, but may also induce increased stellate cell senescence, reducing liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease

et al. 2014

View full text Add to dashboard Cite

“…Prolonged exposure of beta cells to elevated palmitate concentrations has been shown to cause downstream JNK activation and increased p53 expression, events which are in part mediated by enhanced oxidative stress and typically linked to cellular damage [7, 24, 33, this study]. The identification of a p53 response/binding element in the promoter region of p66 Shc indicated that p66 Shc is a p53 target gene and that p66 Shc is indispensable for p53-induced apoptosis [22,23,34]. In this study, murine and human islets, as well as INS-1E cells, showed increased levels of p66 Shc when chronically exposed to elevated palmitate concentrations.…”

Section: Discussionmentioning

confidence: 86%

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis The role of the redox adaptor protein p66 Shc as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. Methods The effects of the FA palmitate on p66 Shc expression were evaluated in human and murine islets and in rat insulinsecreting INS-1E cells. p66 Shc expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66 Shc was investigated using pancreatic islets from p66 Shc−/− mice and in INS-1E cells with knockdown of p66 Shc or overexpression of wildtype and phosphorylation-defective p66 Shc . Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Results Palmitate induced a selective increase in p66 Shc protein expression and phosphorylation on Ser 36 and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66 Shc expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 Shc−/− mice and following p66 Shc knockdown in INS-1E cells; by contrast, overexpression of p66 Shc , but not that of the phosphorylation-defective p66 Shc mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66 Shc were dependent upon its c-Jun N-terminal kinasemediated phosphorylation on Ser 36 and associated with generation of ROS. p66 Shc protein expression and function were also elevated in islets from HFD-fed mice and from obese/ overweight cadaveric human donors. Conclusions/interpretation p53-dependent augmentation of p66 Shc expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

show abstract

p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice

Cited by 103 publications

References 28 publications

Senescence in chronic liver disease: Is the future in aging?

Senescence in chronic liver disease: Is the future in aging?

Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

Contact Info

Product

Resources

About