Väitöstilaisuus (Daniel Nilsson) : insuliiniherkkyyden ja insuliiniresisenssin taustageenejä koeteltiin koe-eläimessä.

*Forkhead genes in adipocytes and podocytes
Nilsson, Daniel
2016-11-18 ( Tämän väitöstilaisuuden kävin kuuntelemassa klo 13 -17 välillä)

Taustaterminologia  Forkhead geenit. Näistä löytyy luettelo  netissäkin: ne kuuluvat transkriptiotekijöihin, joiten joukko on nykyään jo 2-3000, eikä 1500, kuten  edellisessä muistiinpanossani mainitsin blogiin. Näsitä on runsaat  40 Forkhead-geenejä, ryhmän jäseniä. Näistä tutkija valitsi FOXC2 ja FOXF2 lähemmin tutkittavaksi ja niillä on  vastakkaisia metabolisia vaikutuksia.
Työ oli tehty hiirillä, joiden vastaavalla FOXC2.geenillä on ihmisgeenin kanssa 85% homologia.
 https://en.wikipedia.org/wiki/FOX_proteins
Otan tässä kuitenkin esiin tiedot näistä ihmisgeeneistä .

•  Geeni FOX2F. Sijainti kr.625.3.  muut nimet FKHL6, FREAC, FREAC-2. Tätä lötyy keuhksota ja placentasta.   "FOXF2 encodes forkhead box F2, one of many human homologues of the Drosophila melanogaster transcription factor forkhead. FOXF2 is expressed in lung and placenta, and has been shown to transcriptionally activate several lung-specific genes. [provided by RefSeq, Jul 2008]"

Lisätietoa tästä geenistä:  https://www.ncbi.nlm.nih.gov/gene/2295

Siteeraan FOXC2 geenin tietoja tähän alle.

• Geeni FOXC2. Sijainti kr.16q24.1

Muut nimet:  LP, KFH1, MFH-1, FKHL14.
Löytyvää tekstiä: "This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it may play a role in the development of mesenchymal tissues. [provided by RefSeq, Jul 2008]"
https://www.ncbi.nlm.nih.gov/gene/2303 

Related articles in PubMed

1. Correlations of FOXC2 Gene Expression and Polymorphism with Type 2 Diabetes Mellitus. Nian X, et al. Clin Lab, 2016. PMID 27349002
2. Overexpression of transcription factor FOXC2 in cultured human podocytes upregulates injury markers and increases motility. Datta N, et al. Exp Cell Res, 2016 Jan 1. PMID 26524507
3. Effects of forkhead box C2 on carcinogenesis and lymphatic metastasis in endometrial carcinoma. Fan YY, et al. Genet Mol Res, 2015 May 25. PMID 26125751
4. FOXC2 promotes chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition. Zhou Z, et al. Cancer Lett, 2015 Jul 28. PMID 25896630
5. High expression of forkhead box protein C2 is related to poor prognosis in human gliomas. Wang YW, et al. Asian Pac J Cancer Prev, 2014. PMID 25605149
6.  
   GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?
7. Evaluation of FoxC2 expression, alone or in combination with E-cadherin expression, may help to stratify non-small cell lung cancer patients for risk of disease progression, pointing to this EMT regulator as a potential prognostic marker
8. Data indicate the role for altered forkhead box C2 (FoxC2)-Delta-like ligand 4 (Dll4)signaling in structural alterations of saphenous veins in patients with varicose veins.
9. FOXC2 gene is associated with the glycolipid metabolic abnormality in T2DM patients.
10. Adenovirus-mediated FoxC2 expression enhances BMP7-facilitated anabolism in nucleus pulposus cells of the intervertebral discs.
11. The data indicate that the expression of FOXC2 in podocytes needs to be tightly regulated, and that its overexpression induces a chain of cellular events leading to podocyte dysfunction.
12. Peri-tumoral lymphatics were associated with increased lymphatic metastasis. FOXC2 may be associated with the genesis of endometrial carcinoma and lymphangiogensis in endometrial adenocarcinoma in intra- and peri-tumoral lymphatics.
13. our findings contribute to the putative targets in which the FLT4 gene mutation was found to have a significant role in lymphatic filariasis, while FOXC2 and FLT4 SNP interactions need to be further elucidated at a functional level.
14. High FOXC2 expression is associated with tumor proliferation and invasion potential in oral tongue squamous cell carcinoma.
15. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. This was mediated by TAZ and led to cell death.

we propose that Foxc2 is functionally maintained in the cytoplasm of normal epithelial cells by CK2alpha/alpha'-mediated phosphorylation at serine 124, which is dependent on proper targeting of the holoenzyme via the CK2b regulatory subunit.

Insuliiniherkkyys

http://www.ncbi.nlm.nih.gov/pubmed/26333405

J Biosci. 2015 Sep;40(3):593-605.

The emerging roles of inositol pyrophosphates in eukaryotic cell physiology.

Thota SG¹, Bhandari R. Abstract

Inositol pyrophosphates are water soluble derivatives of inositol that contain pyrophosphate or diphosphate moieties in addition to monophosphates.

 The best characterised inositol pyrophosphates, are IP7 (diphosphoinositol pentakisphosphate or PP-IP5), and IP8 (bisdiphosphoinositol tetrakisphosphate or (PP)2-IP4). These energy-rich small molecules are present in all eukaryotic cells, from yeast to mammals, and are involved in a wide range of cellular functions including apoptosis, vesicle trafficking, DNA repair, osmoregulation, phosphate homeostasis, insulin sensitivity, immune signalling, cell cycle regulation, and ribosome synthesis. Identified more than 20 years ago, there is still only a rudimentary understanding of the mechanisms by which inositol pyrophosphates participate in these myriad pathways governing cell physiology and homeostasis.

 The unique stereochemical and bioenergetic properties these molecules possess as a consequence of the presence of one or two pyrophosphate moieties in the vicinity of densely packed monophosphates are likely to form the molecular basis for their participation in multiple signalling and metabolic pathways. The aim of this review is to provide first time researchers in this area with an introduction to inositol pyrophosphates and a comprehensive overview on their cellular functions.

PMID:

26333405

[PubMed - in process] 

 

New horizons in cellular regulation by inositol polyphosphates: insights from the pancreatic β-cell.

Barker CJ, Berggren PO.

Pharmacol Rev. 2013 Feb 19;65(2):641-69. doi: 10.1124/pr.112.006775. Print 2013 Apr. Review.

Studies of inositol polyphosphates in the pancreatic β-cell have led to an exciting synergism between new discoveries regarding their cellular roles and new insights into β-cell function. Because the loss or malfunction of the β-cell is central to diabetes, these studies open the possibility of new pharmacological interventions in a disease that has reached epidemic proportions worldwide. Using the β-cell as our prime but not exclusive example, we examine the inositol polyphosphates in three main groups: 

1) inositol 1,4,5-trisphosphate and its influence on Ca(2+) signaling, specifically in a cell in which cytoplasmic-free Ca(2+) concentration is principally increased by plasma membrane standing voltage-gated Ca(2+) channels; 

2) higher inositol polyphosphates including a novel second messenger inositol 3,4,5,6-tetrakisphosphate and a regulatory role for inositol hexakisphosphate in β-cell Ca(2+) homeostasis and exo- and endocytosis; and

 3) inositol pyrophosphates and their role in β-cell exocytosis, together with the exciting possibility of being novel targets for therapy in diabetes. We conclude with some of the new perspectives that are likely to become apparent in the next few years.Free Article

Similar articles

 

Select item 228840292.

The pancreatic beta cell as a paradigm for advances in inositide research.

Barker CJ, Berggren PO.

Adv Biol Regul. 2012 Sep;52(3):361-8. doi: 10.1016/j.jbior.2012.05.002. Epub 2012 May 26. Review.

In a previous review for Advances in Enzyme Research (Berggren and Barker, 2008) we outlined the history of our involvement in discovering important roles for inositides in the insulin secreting pancreatic beta cell. In this current appraisal we bring the work up to date and project how we believe this field will continue to develop in the future. Recently, we have seen an important synergism between the growth in our understanding of inositide function and our knowledge of beta cell stimulus-secretion coupling in both physiological and pathophysiological contexts. Important advances have been made in three areas.

 1. The classic regulation of cytoplasmic free Ca(2+) concentration [Ca(2+)](i) by Inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) and its receptor,

 2. A novel role of the inositol pyrophosphates, especially 5-diphosphoinositol pentakisphosphate (5-PP-InsP(5)), in exocytosis,

 and 3. The unique signaling roles of PI3K pathways instituted by the engagement of the insulin receptor in an autocrine, positive feed-back loop. We examine each of these in turn and close with an assessment of the likely future directions the research will take.

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Select item 180338843.

Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells.

Illies C, Gromada J, Fiume R, Leibiger B, Yu J, Juhl K, Yang SN, Barma DK, Falck JR, Saiardi A, Barker CJ, Berggren PO.

Science. 2007 Nov 23;318(5854):1299-302.

Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic beta cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (InsP7 or IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in beta cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic beta cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.Free Article

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Kommentti.

Orgaanista fosfaattia, fytiiniä (IP6) saa kasvisperäisestä ravinnosta, lähinnä viljasta, siemenistä, pähkinöistä, kuitulisistä,  jyvistä, hiutaleista, muroista, joita ei ole hiivan fytaaseilla  täysin hajoitettu  vähempifosfaattisiin IPx muotoihin ja epäorgaanisiksi fosfaateiksi  (Pi) .

Fytiinin  hiilirengasta,myo- inositolia  saa kehoon paremmin, kun  sokerin käyttöään  vähentää, sillä tavallinen glukoosi kilpailee sen kanssa soluun pääsystä 

Insuliiniherkkyyden paraneminen treenauksesta korreloi alentuneisiin plasman keramideihin

LÄHDE:  Obesity (Silver Spring). 2015 May 12. doi: 10.1002/oby.21117. [Epub ahead of print]

Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obesity and type 2 diabetes.

Kasumov T¹, Solomon TP², Hwang C², Huang H², Haus JM², Zhang R^3,4, Kirwan JP^1,2,5,6.

Tiivistelmä_ Abstract

AIHE: Tarkoituksena  oli katsoa reenauksen  vaikutusta insuliiniherkkyyteen ja lihavuudellesekä 2- tyypin diabetekselle  tyypilliset keramidit

• ENGL.: OBJECTIVE: To assess the effect of exercise training on insulin sensitivity and plasma ceramides in obesity and type 2 diabetes (T2D).

 MENETELMÄT:  24 aikuista joilla oli lihavuutta ja normaali glukoositoleranssi  (n= 14) tai diabetes ( n= 10)  tutkittiin ennen  testiä ja 12 viikkoa treenausohjelman jälkeen. Treenaus oli 5 kertaa viikossa tunnin päivässä  80- 85% sydämen maksimipulssista.  Mitattiin muutokset kehon kokoomuksessa käyttämällä  hydrostattista punnitusta ja tietokonetomografiaa. Perifeerisen kudoksen  insuliiniherkkyys mitattiin.  Plasman keramidit (C14:0, C16:0,, C18:0, C18:1, C20:0, C24:0,ja C214:1)  mitattiin kvantitatiivisesti.

• ENGL: METHODS: Twenty-four adults with obesity and normal glucose tolerance (NGT, n = 14) or diabetes (n = 10) were studied before and after a 12-week supervised exercise-training program (5 days/week, 1 h/day, 80-85% of maximum heart rate). Changes in body composition were assessed using hydrostatic weighing and computed tomography. Peripheral tissue insulin sensitivity was assessed by a 40 mU/m² /min hyperinsulinemic euglycemic clamp. Plasma ceramides (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1) were quantified using electrospray ionization tandem mass spectrometry after separation with HPLC.

 TULOKSET: Plasman keramidit olivat samanlaisia lihavuudessa ja  normaaliglukoosirasituksessa ja diabeetikoilla, vaikka glukoositoleranssit erosivat.  Treenaus alensi merkitsevästi kehon painoa ja lihavuutta ja kohotti insuliiniherkkyyttä molemmissa ryhmissä. Lisäksi  kaikilla interventioon osallistuneilla laski plasman keramidien  C14:0, C16:0, C18:1  ja C24:9 pitoisuudet . Alenemat kokonaiskeramideissa ja C14:0 keramideissa korreloi negatiiviseeti insuliiniherkkyyteen.  ( herkkyys nousi kun keramidipitoisuudet laskivat)

• ENGL: RESULTS: Plasma ceramides were similar for the subjects with obesity and NGT and the subjects with diabetes, despite differences in glucose tolerance. Exercise significantly reduced body weight and adiposity and increased peripheral insulin sensitivity in both groups (P < 0.05). In addition, plasma C14:0, C16:0, C18:1, and C24:0 ceramide levels were reduced in all subjects following the intervention (P < 0.05). Decreases in total (r = -0.51, P = 0.02) and C14:0 (r = -0.56, P = 0.009) ceramide were negatively correlated with the increase in insulin sensitivity.

 YHTEENVETO: Keramidit linkkiytyvät treenauksen aikaansaamaan  paranemiseen insuliiniherkkyydessä.  Plasman C14:0 keramidi saattaa olla spesifinen kohdekin tutkittaessa lipideihin korreloivaa insuliiniresistenssiä lihavuudessa ja  2-tyypin diabeteksessa.

• CONCLUSIONS: Ceramides are linked to exercise training-induced improvements in insulin sensitivity, and plasma C14:0 ceramide may provide a specific target for investigating lipid-related insulin resistance in obesity and T2D.

© 2015 The Obesity Society.
Suomennos 14.5. 2015