Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.
G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization, integrin activation or integrin signalling. The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.
Hafner
Markus
M
LIMES Program Unit Chemical Biology & Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Germany.
Schmitz
Anton
A
Grüne
Imke
I
Srivatsan
Seergazhi G
SG
Paul
Bianca
B
Kolanus
Waldemar
W
Quast
Thomas
T
Kremmer
Elisabeth
E
Bauer
Inga
I
Famulok
Michael
M
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D052157:Aptamers, Nucleotide; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000302:isolation & purification / Q000494:pharmacology*
D052157:Aptamers, Nucleotide; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C516025:SecinH3; D014230:Triazoles; C100723:cytohesin-1; D020727:ADP-Ribosylation Factors