The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion

Nakatsu, Yusuke; Mori, Kyoichi; Matsunaga, Yasuka; Yamamotoya, Takeshi; Ueda, Koji; Inoue, Yuki; Mitsuzaki-Miyoshi, Keiko; Sakoda, Hideyuki; Fujishiro, Midori; Yamaguchi, Suguru; Kushiyama, Akifumi; Ono, Hiraku; Ishihara, Hideharu; Asano, Tomohiko

doi:10.1074/jbc.m117.780726

Cited by 22 publications

(25 citation statements)

References 36 publications

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“…Immunohistochemistry was performed as previously described 36 . Briefly, paraffin-embedded pancreatic sections were deparaffinized in xylene and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

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The Trk-fused gene (TFG) is reportedly involved in the process of COPII-mediated vesicle transport and missense mutations in TFG cause several neurodegenerative diseases including hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). The high coincidence ratio between HMSN-P and diabetes mellitus suggests TFG to have an important role(s) in glucose homeostasis. To examine this possibility, β-cell specific TFG knockout mice (βTFG KO) were generated. Interestingly, βTFG KO displayed marked glucose intolerance with reduced insulin secretion. Immunohistochemical analysis revealed smaller β-cell masses in βTFG KO than in controls, likely attributable to diminished β-cell proliferation. Consistently, β-cell expansion in response to a high-fat, high-sucrose (HFHS) diet was significantly impaired in βTFG KO. Furthermore, glucose-induced insulin secretion was also markedly impaired in islets isolated from βTFG KO. Electron microscopic observation revealed endoplasmic reticulum (ER) dilatation, suggestive of ER stress, and smaller insulin crystal diameters in β-cells of βTFG KO. Microarray gene expression analysis indicated downregulation of NF-E2 related factor 2 (Nrf2) and its downstream genes in TFG depleted islets. Collectively, TFG in pancreatic β-cells plays a vital role in maintaining both the mass and function of β-cells, and its dysfunction increases the tendency to develop glucose intolerance.

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“…Immunohistochemistry was performed as previously described 36 . Briefly, paraffin-embedded pancreatic sections were deparaffinized in xylene and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

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“…In mice it has been shown that PIN1 becomes upregulated in response to high glucose (123), insulin, and a high-fat diet (124, 125) and that it manages metabolic responses to diet and hormone stimulation (125, 126). Intriguingly, PIN1 augments the uptake of triglycerides and fosters differentiation of MEFs into adipose cells in response to insulin, whereas PIN1KO mice are insulin resistant, have glucose intolerance and display lower adipose tissue weight when fed with high fat diet (125).…”

Section: Impact Of Pin1-mediated Prolyl-isomerization On Cellular Promentioning

confidence: 99%

Oncogenic Hijacking of the PIN1 Signaling Network

et al. 2019

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Cellular choices are determined by developmental and environmental stimuli through integrated signal transduction pathways. These critically depend on attainment of proper activation levels that in turn rely on post-translational modifications (PTMs) of single pathway members. Among these PTMs, post-phosphorylation prolyl-isomerization mediated by PIN1 represents a unique mechanism of spatial, temporal and quantitative control of signal transduction. Indeed PIN1 was shown to be crucial for determining activation levels of several pathways and biological outcomes downstream to a plethora of stimuli. Of note, studies performed in different model organisms and humans have shown that hormonal, nutrient, and oncogenic stimuli simultaneously affect both PIN1 activity and the pathways that depend on PIN1-mediated prolyl-isomerization, suggesting the existence of evolutionarily conserved molecular circuitries centered on this isomerase. This review focuses on molecular mechanisms and cellular processes like proliferation, metabolism, and stem cell fate, that are regulated by PIN1 in physiological conditions, discussing how these are subverted in and hijacked by cancer cells. Current status and open questions regarding the use of PIN1 as biomarker and target for cancer therapy as well as clinical development of PIN1 inhibitors are also addressed.

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“…Indeed, Pin1 null mice exhibit impairments of both glucose and insulin tolerance [49]. In addition, Pin1 is a key player in the release of insulin, as Pin1 deletion in islets alleviates insulin release in response to high glucose [50]. In contrast, adipocyte-specific Pin1 knockout (KO) mice have lower body weights, with liver triglyceride and macrophage infiltration of epididymal white adipose tissue when fed a HFD [37].…”

Section: Essential Role Of Adipose Pin1 In Obesity and Nash Developmentmentioning

confidence: 99%

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

Inoue

Nakatsu

Yamamotoya

et al. 2019

Cells

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Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly resistant to non-alcoholic steatohepatitis (NASH) development by either a high-fat diet or methionine–choline-deficient diet feeding. The processes of NASH development can basically be separated into lipid accumulation and subsequent fibrotic change with inflammation. In this review, we outline the molecular mechanisms by which increased Pin1 promotes both of these phases of NASH. The target proteins of Pin1 involved in lipid accumulation include insulin receptor substrate 1 (IRS-1), AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase 1 (ACC1), while the p60 of the NF-kB complex and transforming growth factor β (TGF-β) pathway appear to be involved in the fibrotic process accelerated by Pin1. Interestingly, Pin1 deficiency does not cause abnormalities in liver size, appearance or function. Therefore, we consider the inhibition of increased Pin1 to be a promising approach to treating NASH and preventing hepatic fibrosis.

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The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion

Cited by 22 publications

References 36 publications

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Oncogenic Hijacking of the PIN1 Signaling Network

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

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