Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes

Amar Abderrahmani; Loic Yengo; Robert Caiazzo; Mickael Canouil; Stephane Cauchi; Violeta Raverdy; Valerie Plaisance; Valerie Pawlowski; Stephane Lobbens; Julie Maillet; Laure Rolland; Raphael Boutry; Gurvan Queniat; Maxime Kwapich; Mathie Tenenbaum; Julien Bricambert; Sophie Saussenthaler; Elodie Anthony; Pooja Jha; Julien Derop; Olivier Sand; Iandry Rabearivelo; Audrey Leloire; Marie Pigeyre; Martine Daujat-Chavanieu; Sabine Gerbal-Chaloin; Tasnim Dayeh; Guillaume Lassailly; Philippe Mathurin; Bart Staels; Johan Auwerx; Annette Schurmann; Catherine Postic; Clemens Schafmayer; Jochen Hampe; Amelie Bonnefond; Francois Pattou; Philippe Froguel

arXiv · 1712.04680

Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes

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Abstract

Type 2 diabetes (T2D) is closely linked with non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance, but the involved mechanisms are still elusive. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that both hypomethylation at a CpG site in PDGFA (encoding platelet derived growth factor alpha) and PDGFA overexpression are associated with increased T2D risk, hyperinsulinemia, increased insulin resistance and increased steatohepatitis risk. Both genetic risk score studies and human cell modeling pointed to a causative impact of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of both insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA blocking antibodies, PDGF receptor inhibitors and by metformin opening therapeutic avenues. Conclusion: Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and NAFLD.

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Amar Abderrahmani, Loic Yengo, Robert Caiazzo, Mickael Canouil, Stephane Cauchi, Violeta Raverdy, Valerie Plaisance, Valerie Pawlowski, Stephane Lobbens, Julie Maillet, Laure Rolland, Raphael Boutry, Gurvan Queniat, Maxime Kwapich, Mathie Tenenbaum, Julien Bricambert, Sophie Saussenthaler, Elodie Anthony, Pooja Jha, Julien Derop, Olivier Sand, Iandry Rabearivelo, Audrey Leloire, Marie Pigeyre, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Tasnim Dayeh, Guillaume Lassailly, Philippe Mathurin, Bart Staels, Johan Auwerx, Annette Schurmann, Catherine Postic, Clemens Schafmayer, Jochen Hampe, Amelie Bonnefond, Francois Pattou, Philippe Froguel. 2017-12-13. Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes. https://arxiv.org/abs/1712.04680

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