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Disruption of cyclophilin D-mediated calcium transfer from the ER to mitochondria contributes to hepatic ER stress and insulin resistance.
MedLine Citation:
PMID:  23212687     Owner:  NLM     Status:  Publisher    
The role of intracellular calcium (Ca(2+) ) signaling in the control of insulin sensitivity remains unclear. Based on the recently observed role of the mitochondrial chaperone cyclophilin D in regulating Ca(2+) , endoplasmic reticulum (ER), and glucose homeostasis, we used cyclophilin D knock-out (cypD-KO) mice to study the role of inositol 1,4,5-triphosphate receptor (IP3R)-mediated Ca(2+) signaling in hepatic ER stress-induced insulin resistance. We showed that the loss of cypD function induced the hepatic ER stress responsible for increased lipogenesis, insulin resistance and altered glucose homeostasis. Indeed, reduction of ER stress by taurine-conjugated ursodeoxycholic acid treatment or by Grp78 adenoviral overexpression improved hepatic insulin sensitivity and glucose metabolism. Interestingly, we demonstrated that cypD-related ER stress was associated with a limitation of histamine-stimulated Ca(2+) transfer from ER to mitochondria in isolated hepatocytes of cypD-KO mice. In addition, we showed that cypD regulated Ca(2+) fluxes between ER and mitochondria by interacting with the IP3R-Grp75-VDAC Ca(2+) channelling complex. Lastly, pharmacological and genetic inhibition of cypD concomitantly reduced its interaction with this Ca(2+) channeling complex, inhibited Ca(2+) exchange between ER and mitochondria, induced ER stress and altered insulin signaling in HuH7 cells, confirming strong inter-relationships between these effects. CypD-related alterations of insulin signaling are mediated by activation of PKCε rather than by JNK activation. Conclusion: Our results identify cypD as an important regulator of Ca(2+) exchange between ER and mitochondria and demonstrate that the disruption of IP3R-mediated Ca(2+) signaling induced by the inhibition of cypD triggers ER stress and hepatic insulin resistance. (HEPATOLOGY 2012.).
Jennifer Rieusset; Jeremy Fauconnier; Melanie Paillard; Elise Belaidi; Emily Tubbs; Marie-Agnès Chauvin; Annie Durand; Amélie Bravard; Geoffrey Teixeira; Birke Bartosch; Maud Michelet; Pierre Theurey; Guillaume Vial; Marie Demion; Emilie Blond; Fabien Zoulim; Ludovic Gomez; Hubert Vidal; Alain Lacampagne; Michel Ovize
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-5
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 American Association for the Study of Liver Diseases.
INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Facultés de médecine Rockefeller et Charles Merieux Lyon-Sud, Lyon, F-69003.
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