Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes

被引：67

作者：

Abderrahmani, Amar ^{[1
,2
]}

Yengo, Loic ^{[1
]}

Caiazzo, Robert ^{[3
]}

Canouil, Mickael ^{[1
]}

Cauchi, Stephane ^{[1
]}

Raverdy, Violeta ^{[3
]}

Plaisance, Valerie ^{[1
]}

Pawlowski, Valerie ^{[1
]}

Lobbens, Stephane ^{[1
]}

Maillet, Julie ^{[1
]}

Rolland, Laure ^{[1
]}

Boutry, Raphael ^{[1
]}

Queniat, Gurvan ^{[1
]}

Kwapich, Maxime ^{[1
]}

Tenenbaum, Mathie ^{[1
]}

Bricambert, Julien ^{[1
]}

Saussenthaler, Sophie ^{[4
,5
]}

Anthony, Elodie ^{[6
]}

Jha, Pooja ^{[7
]}

Derop, Julien ^{[1
]}

Sand, Olivier ^{[1
]}

Rabearivelo, Iandry ^{[1
]}

Leloire, Audrey ^{[1
]}

Pigeyre, Marie ^{[3
]}

Daujat-Chavanieu, Martine ^{[8
]}

Gerbal-Chaloin, Sabine ^{[8
]}

Dayeh, Tasnim ^{[9
]}

Lassailly, Guillaume ^{[10
]}

Mathurin, Philippe ^{[10
]}

Staels, Bart ^{[11
]}

Auwerx, Johan ^{[7
]}

Schuermann, Annette ^{[4
,5
]}

Postic, Catherine ^{[6
]}

Schafmayer, Clemens ^{[12
]}

Hampe, Jochen ^{[13
]}

Bonnefond, Amelie ^{[1
,2
]}

Pattou, Francois ^{[3
]}

Froguel, Philippe ^{[1
,2
]}

机构：

[1] Univ Lille, CNRS, Inst Pasteur Lille, UMR 8199,European Genom Inst Diabet, Lille, France

[2] Imperial Coll London, Dept Med, Sect Genom Common Dis, London, England

[3] Univ Lille, INSERM, CHU Lille, U1190,European Genom Inst Diabet, Lille, France

[4] German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany

[5] German Ctr Diabet Res DZD, Munich, Germany

[6] Univ Paris 05, Sorbonne Paris Cite, UMR 8104, CNRS,Inserm,U1016,Inst Cochin, Paris, France

[7] Ecole Polytech Fed Lausanne, Lab Integrat Syst Physiol, Lausanne, Switzerland

[8] Univ Montpellier, INSERM, Inst Regenerat Med & Biotherapy, CHU Montpellier,U1183, Montpellier, France

[9] Skane Univ Hosp Malmo, Dept Clin Sci, Malmo, Sweden

[10] Univ Lille, INSERM, CHU Lille, U995,Lille Inflammat Res Int Ctr, Lille, France

[11] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,U1011,European Genom Inst Diab, Lille, France

[12] Univ Hosp Schleswig Holstein, Dept Visceral & Thorac Surg, Kiel, Germany

[13] Tech Univ Dresden, Med Dept 1, Dresden, Germany

来源：

DIABETES | 2018年 / 67卷 / 07期

基金：

欧洲研究理事会; 欧盟地平线“2020”;

关键词：

ALTERED DNA METHYLATION; KINASE-C-EPSILON; FATTY LIVER; IMATINIB MESYLATE; GLYCEMIC TRAITS; DISEASE; ACTIVATION; FIBROSIS; GLUCOSE; GENES;

D O I：

10.2337/db17-1539

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor ) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the 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 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. 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 possibly NAFLD.

引用

页码：1310 / 1321

页数：12

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