PEDF-induced alteration of metabolism leading to insulin resistance

Carnagarin, Revathy; Dharmarajan, Arun; Dass, Crispin R.

doi:10.1016/j.mce.2014.11.006

Cited by 29 publications

(23 citation statements)

References 85 publications

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“…We observed a significant increase in serum PEDF in the Serpinf1 −/− mice injected with 5×10 12 VP/kg of HDAd -SERPINF1. Previous work by others showed that overexpression of Serpinf1 led to metabolic dysfunction, with increased body weight and impaired glucose tolerance (16-18). To determine whether the PEDF produced by the liver was biologically active, we measured the body weights of mice injected with control (PBS) and HDAd -SERPINF1 at 3 and 6 months of age and performed an intraperitoneal glucose tolerance test (IP GTT).…”

Section: Resultsmentioning

confidence: 99%

Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice

Rajagopal

Homan

Joeng

et al. 2016

Molecular Genetics and Metabolism

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Osteogenesis imperfecta (OI) is a group of genetic disorders characterized by bone fragility and deformity. OI type VI is unique owing to the mineralization defects observed in patient biopsies. Furthermore, it has been reported to respond less well to standard therapy with bisphosphonates (1). Others and we have previously identified SERPINF1 mutations in patients with OI type VI. SERPINF1 encodes pigment epithelium derived factor (PEDF), a secreted collagen-binding glycoprotein that is absent in the sera of patients with OI type VI. Serpinf1 null mice show increased osteoid and decreased bone mass, and thus recapitulate the OI type VI phenotype. We tested whether restoration of circulating PEDF in the blood could correct the phenotype of OI type VI in the context of protein replacement. To do so, we utilized a helper-dependent adenoviral vector (HDAd) to express human SERPINF1 in the mouse liver and assessed whether PEDF secreted from the liver was able to rescue the bone phenotype observed in Serpinf1−/− mice. We confirmed that expression of SERPINF1 in the liver restored the serum level of PEDF. We also demonstrated that PEDF secreted from the liver was biologically active by showing the expected metabolic effects of increased adiposity and impaired glucose tolerance in Serpinf1−/− mice. Interestingly, overexpression of PEDF in vitro increased mineralization with a concomitant increase in the expression of bone gamma-carboxyglutamate protein, alkaline phosphatase and collagen, type I, alpha I, but the increased serum PEDF level did not improve the bone phenotype of Serpinf1−/− mice. These results suggest that PEDF may function in a context-dependent and paracrine fashion in bone homeostasis.

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Section: Resultsmentioning

confidence: 99%

Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice

Rajagopal

Homan

Joeng

et al. 2016

Molecular Genetics and Metabolism

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“…Thus, PEDF may be a potential therapeutic target in ameliorating insulin resistance (Carnagarin et al, 2015).…”

Section: Pigment Epithelium-derived Factor (Pedf)mentioning

confidence: 99%

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment

2015

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Adipose tissue is recognized as an active endocrine organ that produces a number of endocrine substances referred to as "adipokines" including leptin, adiponectin, adipolin, visfatin, omentin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), resistin, pigment epithelium-derived factor (PEDF), and progranulin (PGRN) which play an important role in the food intake regulation and significantly influence insulin sensitivity and in some cases directly affect insulin resistance in skeletal muscle, liver, and adipose tissue. The review summarizes current knowledge about adipose tissue-derived hormones and their influence on energy homeostasis regulation. The possible therapeutic potential of these adipokines in the treatment of insulin resistance, endothelial dysfunction, a pro-inflammatory response, obesity, eating disorders, progression of atherosclerosis, type 1 diabetes, and type 2 diabetes is discussed.

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“…PEDF has been originally identified in the retina, however, it has now become evident that it is expressed throughout the human body and is constantly present in the systemic circulation [4,5]. Studies in the past years have implicated PEDF in the pathophysiology of a wide range of angiogenesis-associated disorders, including diabetic complications [6,7], macular degeneration [8,9], Osteogenesis Imperfecta Type VI [10,11], and the growth of many types of solid tumors [12][13][14][15][16]. Some of these roles may be mediated by the effect of PEDF on stem cells as was shown in the brain, muscle, and eye [11].…”

Section: Introductionmentioning

confidence: 99%

Pigment Epithelium-Derived Factor and its Phosphomimetic Mutant Induce JNK-Dependent Apoptosis and P38-Mediated Migration Arrest

Konson

Pradeep

D’Acunto

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pigment epithelium-derived factor (PEDF) is a potent endogenous inhibitor of angiogenesis, and a promising anticancer agent. We have previously shown that PEDF can be phosphorylated, and that distinct phosphorylations differentially regulate its physiological functions. We also demonstrated that triple phosphomimetic mutant (EEE-PEDF), has significantly increased antiangiogenic activity, and is much more efficient than WT-PEDF in inhibiting neovascularization and tumor growth. The enhanced antiangiogenic effect was associated with a direct ability to facilitate apoptosis of tumor-residing endothelial cells (EC), and subsequently, disruption of intratumoral vascularization. In the present report, we elucidated the molecular mechanism by which EEE-PEDF exerts more profound effects at the cellular level. Methods: Here we used Western blotting, as well as in vitro binding, proliferation, apoptosis and migration assays to follow the signaling components responsible for the PEDF and EEE-PEDF effects. Results: We found that EEE-PEDF suppresses EC proliferation due to caspase-3-dependent apoptosis, and also inhibits migration of the EC much better than WT-PEDF. Although WT-PEDF and EEE-PEDF did not affect proliferation and did not induce apoptosis of cancer cells, these agents efficiently inhibited cancer cell motility, with EEE-PEDF showing stronger effect. The stronger activity of EEE-PEDF was correlated to a better binding to laminin receptors. Furthermore, the proapoptotic and antimigratory activities of WT-PEDF and EEE-PEDF were found respectively regulated by differential activation of two distinct MAPK pathways, namely JNK and p38. We show that JNK and p38 phosphorylation is much higher in cells treated with EEE-PEDF. JNK leads to apoptosis of ECs, while p38 leads to antimigratory effect in both EC and cancer cells. Conclusion: These results reveal the molecular signaling mechanism by which the phosphorylated PEDF exerts its stronger antiangiogenic, antitumor activities.

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PEDF-induced alteration of metabolism leading to insulin resistance

Cited by 29 publications

References 85 publications

Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice

Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment

Pigment Epithelium-Derived Factor and its Phosphomimetic Mutant Induce JNK-Dependent Apoptosis and P38-Mediated Migration Arrest

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