Imperial College London
Portrait Picture

Emeritus ProfessorStephenFranks

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Emeritus Professor of Reproductive Endocrinology
 
 
 
//

Contact

 

+44 (0)20 7594 2109s.franks Website

 
 
//

Assistant

 

Miss Kiran Dosanjh +44 (0)20 7594 4217

 
//

Location

 

5009Institute of Reproductive and Developmental BiologyHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Kwok:2019:10.1101/224485,
author = {Kwok, A and Zvetkova, I and Virtue, S and Huang-Doran, I and Tomlinson, P and Bulger, DA and Hart, D and Knox, R and Franks, S and Voshol, P and Vidal-Puig, A and Sferruzzi-Perri, AN and Jensen, J and ORahilly, S and Semple, RK},
doi = {10.1101/224485},
journal = {BMJ Open},
title = {C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia},
url = {http://dx.doi.org/10.1101/224485},
year = {2019}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Summary</jats:title><jats:p>Heterodimeric class IA phosphatidylinositol-3-kinases (PI3K) transduce signals from many receptor tyrosine kinases including the insulin receptor. PI3K recruitment to phosphotyrosines is mediated by <jats:italic>Pik3r1</jats:italic> gene products including the most intensely studied PI3K regulatory subunit, p85α, which also binds and regulates the PIP3 phosphatase <jats:italic>Pten,</jats:italic> and the lipogenic transcription factor <jats:italic>Xbp1.</jats:italic> Mutations in human <jats:italic>PIK3R1</jats:italic> cause SHORT syndrome, featuring lipodystrophy and severe insulin resistance which, uniquely, are uncoupled from fatty liver and dyslipidemia. We describe a novel mouse model of SHORT syndrome made by knock in of the <jats:italic>Pik3r1</jats:italic> Y657X mutation. Homozygous embryos die at E11.5, while heterozygous mice exhibit pre-and postnatal growth impairment with diminished placental vascularity. Adipose tissue accretion on high fat feeding was reduced, however adipocyte size was unchanged and preadipocyte differentiation <jats:italic>ex vivo</jats:italic> unimpaired. Despite severe insulin resistance, heterozygous mice were hypolipidemic, and plasma adiponectin, liver weight, cholesterol, glycogen and triglyceride content were unchanged. Mild downregulation of lipogenic <jats:italic>Srebp1, Srebp2</jats:italic> and <jats:italic>Chrebp</jats:italic> transcriptional activity but no suppression of <jats:italic>Xbp1</jats:italic> target genes was seen after fasting. These findings give new insights into the developmental role of <jats:italic>Pik3r1,</jats:italic> and establish a model of lipodystrophic insulin resistance dissociated from dyslipidemia as seen in SHORT syndrome.</jats:p>
AU  - Kwok,A
AU  - Zvetkova,I
AU  - Virtue,S
AU  - Huang-Doran,I
AU  - Tomlinson,P
AU  - Bulger,DA
AU  - Hart,D
AU  - Knox,R
AU  - Franks,S
AU  - Voshol,P
AU  - Vidal-Puig,A
AU  - Sferruzzi-Perri,AN
AU  - Jensen,J
AU  - ORahilly,S
AU  - Semple,RK
DO  - 10.1101/224485
PY  - 2019///
SN  - 2044-6055
TI  - C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia
T2  - BMJ Open
UR  - http://dx.doi.org/10.1101/224485
ER  -
Download