Prolyl Isomerase Pin1 Negatively Regulates AMP-activated Protein Kinase (AMPK) by Associating with the CBS Domain in the γ Subunit

Kushiyama

et al. 2017

Sci Rep

Self Cite

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.

Section: Methodsmentioning

confidence: 99%

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

Kushiyama

et al. 2017

Sci Rep

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“…Third, Pin1 reportedly associates with the CBS domain in the γ subunit and reduces AMPKα subunit phosphorylation [43]. The reduction in AMPKα subunit phosphorylation mediated by Pin1 is likely due to the protective effect exerted by AMP or ADP, against dephosphorylation by protein phosphatase 2C (PP2C), being abolished.…”

Section: Role Of Pin1 In the Pathogenesis Of Hepatic Steatosismentioning

confidence: 98%

“…The reduction in AMPKα subunit phosphorylation mediated by Pin1 is likely due to the protective effect exerted by AMP or ADP, against dephosphorylation by protein phosphatase 2C (PP2C), being abolished. As a result, Pin1 negatively regulates AMPK activity [43]. AMPK, known as a major controller of lipid metabolism, directly phosphorylates ACC1 at the Ser79 site, and decreases both its activity and the productions of malonyl-CoA [44,45].…”

Section: Role Of Pin1 In the Pathogenesis Of Hepatic Steatosismentioning

confidence: 99%

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

Inoue

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.

“…Phosphorylation of the α subunit in AMPK is also regulated by Pin1 [ 77 ]. Pin1 overexpression was shown to remarkably decrease, while Pin1 knockdown enhanced, AMPK phosphorylation by 2-deoxy-glucose (2-DG).…”

Section: Pin1 Is Essential For Adipogenesis and Is Involved In Obementioning

confidence: 99%

Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations

Matsunaga

et al. 2016

IJMS

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Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14). Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer’s disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-κB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions.