Disruption of cyclophilin D-mediated calcium transfer from the ER to mitochondria contributes to hepatic ER stress and insulin resistance

Abstract

The role of intracellular calcium (Ca²⁺) signaling in the control of insulin sensitivity remains unclear. Based on the recently observed role of the mitochondrial chaperone cyclophilin D in regulating Ca²⁺, 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 Ca²⁺ 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 Ca²⁺ transfer from ER to mitochondria in isolated hepatocytes of cypD-KO mice. In addition, we showed that cypD regulated Ca²⁺ fluxes between ER and mitochondria by interacting with the IP3R-Grp75-VDAC Ca²⁺ channelling complex. Lastly, pharmacological and genetic inhibition of cypD concomitantly reduced its interaction with this Ca²⁺ channeling complex, inhibited Ca²⁺ 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 Ca²⁺ exchange between ER and mitochondria and demonstrate that the disruption of IP3R-mediated Ca²⁺ signaling induced by the inhibition of cypD triggers ER stress and hepatic insulin resistance. (HEPATOLOGY 2012.)