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Open AccessArticle

Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response

1
CarMeN Laboratory, INSERM U1060, INRA U1397, University Lyon 1, 69008 Lyon, France
2
HP2 Laboratory, INSERM U 1042, University Grenoble Alpes, 38000 Grenoble, France
3
Cancer Research Centre (CRCL), INSERM U1052, 69008 Lyon, France
4
Laboratory of Fundamental and Applied Bioenergetics (LBFA), INSERM U 1055, University Grenoble Alpes, 38000 Grenoble, France
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1319; https://doi.org/10.3390/cells8111319
Received: 13 September 2019 / Revised: 7 October 2019 / Accepted: 22 October 2019 / Published: 25 October 2019
Under physiological conditions, nitric oxide (NO) produced by the endothelial NO synthase (eNOS) upregulates hepatic insulin sensitivity. Recently, contact sites between the endoplasmic reticulum and mitochondria named mitochondria-associated membranes (MAMs) emerged as a crucial hub for insulin signaling in the liver. As mitochondria are targets of NO, we explored whether NO regulates hepatic insulin sensitivity by targeting MAMs. In Huh7 cells, primary rat hepatocytes and mouse livers, enhancing NO concentration increased MAMs, whereas inhibiting eNOS decreased them. In vitro, those effects were prevented by inhibiting protein kinase G (PKG) and mimicked by activating soluble guanylate cyclase (sGC) and PKG. In agreement with the regulation of MAMs, increasing NO concentration improved insulin signaling, both in vitro and in vivo, while eNOS inhibition disrupted this response. Finally, inhibition of insulin signaling by wortmannin did not affect the impact of NO on MAMs, while experimental MAM disruption, using either targeted silencing of cyclophilin D or the overexpression of the organelle spacer fetal and adult testis-expressed 1 (FATE-1), significantly blunted the effects of NO on both MAMs and insulin response. Therefore, under physiological conditions, NO participates to the regulation of MAM integrity through the sGC/PKG pathway and concomitantly improves hepatic insulin sensitivity. Altogether, our data suggest that the induction of MAMs participate in the impact of NO on hepatocyte insulin response. View Full-Text
Keywords: mitochondria-associated endoplasmic reticulum membranes; nitric oxide; cyclic guanosine monophosphate (cGMP)-dependent protein kinase; hepatic glucose metabolism; metabolic flexibility mitochondria-associated endoplasmic reticulum membranes; nitric oxide; cyclic guanosine monophosphate (cGMP)-dependent protein kinase; hepatic glucose metabolism; metabolic flexibility
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Bassot, A.; Chauvin, M.-A.; Bendridi, N.; Ji-Cao, J.; Vial, G.; Monnier, L.; Bartosch, B.; Alves, A.; Cottet-Rousselle, C.; Gouriou, Y.; Rieusset, J.; Morio, B. Regulation of Mitochondria-Associated Membranes (MAMs) by NO/sGC/PKG Participates in the Control of Hepatic Insulin Response. Cells 2019, 8, 1319.

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