Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Inoue, Masakí; Nakatsu, Yusuke; Yamamotoya, Takeshi; Hasei, Shun; Kanamoto, Mayu; Naitou, Miki; Matsunaga, Yasuka; Sakoda, Hideyuki; Fujishiro, Midori; Ono, Hiraku; Kushiyama, Akifumi; Asano, Tomohiko

doi:10.3390/cells8121545

Cited by 13 publications

(13 citation statements)

References 99 publications

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“…In NASH patients, Pin1 was also associated with fibrosis. It has been shown that TGF-β, connective tissue growth factor, and the profibrogenic cytokines promoting fibrosis significantly decreased in Pin1-deficient mice, completely repressing fibrosis markers (10,18). Our study confirmed an association between serum Pin1 level and liver inflammation and fibro- sis in patients with HCV (genotype 1b) infection.…”

Section: Discussionsupporting

confidence: 85%

Serum Peptidyl-prolyl Cis-trans Isomerase NIMA-interacted 1 (Pin1) as a Non-invasive Marker for Liver Fibrosis due to Chronic Hepatitis C Virus.

Cengiz¹,

Özeni̇rler

2021

Hepat Mon

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Background: Hepatitis C virus (HCV) may remain asymptomatic or cause liver fibrosis and cirrhosis. Objectives: We aimed to assess the relationship between serum peptidyl-prolyl cis-trans isomerase NIMA-interacted 1 (Pin1) levels and liver fibrosis due to HCV. Methods: Serum samples of successive patients with HCV genotype 1b and healthy volunteers were collected, and Pin1 levels were measured using ELISA kits. Liver fibrosis stages were calculated by the Ishak Scoring System and subdivided into two groups; stage < 3 (mild fibrosis) and ≥ 3 (advanced fibrosis). Correlation and area under receiver operating characteristics (AUROC) analysis were used to investigate the relationship between Pin1 and clinical and histopathological properties of HCV infection. Results: Ninety-four patients with HCV and 47 age- and sex-matched volunteers were included. The median age of the participants was 52, and 55% of whom were females. The mean (SD) of Pin1 serum level was significantly higher in the HCV group compared with healthy volunteers (33.94 (21.15) vs. 26.82 (8.85) pg/mL, respectively, P = 0.007). Seventy-seven (82%) and 17 (18%) of the participants showed mild and advanced fibrosis, respectively. Pin1 serum levels were significantly lower in the mild compared with advanced fibrosis group (29 (17.88) vs. 43.59 (7.98) pg/mL, respectively, P < 0.001). We found a significantly positive correlation between Pin1 serum level and liver fibrosis stage (r = 0.71, P < 0.001). The cut off of 33.04 pg/mL of Pin1 serum level showed the best sensitivity (100%) and specificity (68.4%) (AUROC = 0.81 [95% confidence interval: 0.72 - 0.90], P < 0.001) for distinguishing advanced from mild liver fibrosis. Conclusions: Serum Pin1 level may be a relevant marker for predicting liver fibrosis in HCV infected patients.

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Section: Discussionsupporting

confidence: 85%

Serum Peptidyl-prolyl Cis-trans Isomerase NIMA-interacted 1 (Pin1) as a Non-invasive Marker for Liver Fibrosis due to Chronic Hepatitis C Virus.

Cengiz¹,

Özeni̇rler

2021

Hepat Mon

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“…Pin1 reportedly affects substrate stability, and regulates TGF-β1 expression, thus enhancing TGF-β1-mediated fibrogenesis signaling (Matsuura et al . 2010 ; Inoue et al 2019 ). In cells expressing BAFF-R H159Y , rBAFF stimulation increased the growth and survival of cells through the regulation of relevant genes including Pin1 (Secreto et al .…”

Section: Resultsmentioning

confidence: 99%

“…Pin1 retained the WW domains (residues 1-39) at the Nterminal and the PPIase domain (residues 45-163) at the Cterminals (Verdecia et al 2000;Chen et al 2018). Pin1 reportedly affects substrate stability, and regulates TGF-β1 expression, thus enhancing TGF-β1-mediated fibrogenesis signaling (Matsuura et al 2010;Inoue et al 2019). In cells expressing BAFF-R H159Y , rBAFF stimulation increased the growth and survival of cells through the regulation of relevant genes including Pin1 (Secreto et al 2014).…”

Section: Baff-r Was Significantly Upregulated On Primarymentioning

confidence: 99%

BAFF signaling drives interstitial transformation of mouse renal tubular epithelial cells in a Pin1-dependent manner

Song

et al. 2021

In Vitro Cell.Dev.Biol.-Animal

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Aberrant expression of B cell–activating factor belonging to TNF superfamily (BAFF) and its receptors results in abnormal biological activities in hematopoietic and non-hematopoietic cells and is closely associated with the occurrence and development of various diseases. However, the biological significance and potential mechanisms underlying BAFF signaling in renal tubular epithelial cells (RTECs) remain unknown. This study aimed to investigate the biological role of BAFF signaling in RTECs. Mice primary RTECs were applied. The proliferation status and apoptotic rates were examined by MTS assay and flow cytometry, respectively. The expression of BAFF and its receptors was analyzed via flow cytometry and sodium ion transport function, and cytokeratin-18 expression was detected through immunofluorescence staining. In addition, Pin1 was knocked down via siRNA and its expression was assessed through reverse transcription PCR. Lastly, western blotting was performed to analyze E-cadherin, ɑ-SMA, and Pin1 expression. Results suggested that BAFF-R was significantly upregulated upon IFN-γ stimulation, and enhancement of BAFF signaling promoted cell survival and reduced their apoptotic rate, while simultaneously reducing the epithelial phenotype and promoting the interstitial transformation of cells. Furthermore, Pin1 was significantly increased, along with the upregulation of BAFF signaling in the RTECs, and participated in interstitial transformation induced by BAFF signaling. Collectively, the present results elucidate the potential mechanism of loss of normal function of RTECs under long-term high dose of BAFF stimulation provides a potential therapeutic target for renal interstitial fibrosis, and underlining mechanisms of shortening of long-term outcomes of kidney allografts via augmenting of BAFF signaling.

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“…The difference in mouse age and the dosage of LPS, which may be the reason for our different results. In fact, except for some cancers, Pin1 also plays an important role in asthma development and in the response to microbial infection besides rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE) and nonalcoholic steatohepatitis (NASH) (39)(40)(41)(42)(43)(44), suggesting that Pin1 is closely related to certain inflammatory reactions. Our study offers clues for understanding septic shock pathogenesis and might impact on the future diagnosis and treatment of patients with inflammatory disease.…”

Section: Discussionmentioning

confidence: 99%

Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock

et al. 2021

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Pin1 is the only known peptidyl-prolyl cis-trans isomerase (PPIase) that can specifically recognize and isomerize the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif, change the conformation of proteins through protein phosphorylation, thus regulate various cellular processes in the body. Pin1 plays an important role in cancer, Alzheimer’s disease, and autoimmune diseases. However, the specific mechanism of Pin1 regulation in LPS-induced septic shock is unclear. Here, we found that lack of Pin1 reduced shock mortality and organ damage in mice, and NLRP3 inflammasome activation also was reduced in this process. We further confirmed that Pin1 can affect the expression of NLRP3, ASC, Caspase1, and this process can be regulated through the p38 MAPK pathway. We analyzed that p38 MAPK signaling pathway was highly expressed in septic shock and showed a positive correlation with Pin1 in the Gene Expression Omnibus database. We found that Pin1 could affect the phosphorylation of p38 MAPK, have no obvious difference in extracellular signal-regulated kinases (ERK) and Jun-amino-terminal kinase (JNK) signaling. We further found that Pin1 and p-p38 MAPK interacted, but not directly. In addition, Pin1 deficiency inhibited the cleavage of gasdermin D (GSDMD) and promoted the death of macrophages with LPS treatment, and reduced secretion of inflammatory cytokines including IL-1β and IL-18. In general, our results suggest that Pin1 regulates the NLRP3 inflammasome activation by p38 MAPK signaling pathway in macrophages. Thus, Pin1 may be a potential target for the treatment of inflammatory diseases such as septic shock.

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Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Cited by 13 publications

References 99 publications

Serum Peptidyl-prolyl Cis-trans Isomerase NIMA-interacted 1 (Pin1) as a Non-invasive Marker for Liver Fibrosis due to Chronic Hepatitis C Virus.

Serum Peptidyl-prolyl Cis-trans Isomerase NIMA-interacted 1 (Pin1) as a Non-invasive Marker for Liver Fibrosis due to Chronic Hepatitis C Virus.

BAFF signaling drives interstitial transformation of mouse renal tubular epithelial cells in a Pin1-dependent manner

Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock

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