Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes
نویسندگان
چکیده
281 words) 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,
منابع مشابه
The Role of Fetuin-A in Diabetes and Obesity: The Mechanism and Action
Fetuin-A is a phosphorylated glycoprotein produced by liver.It by binding to calcium ion inhibits ectopic calcium deposition and protects vascular calcification. Fetuin-A acts as a multifactorial protein and its role has been documented from brain development to bone remodeling and immune function, regulation of insulin activity, hepatocyte growth factor activity and inhibition lymphocyte blast...
متن کاملMesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance.
Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide eviden...
متن کاملEstrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity.
The development of insulin resistance in the liver is a key event that drives dyslipidemia and predicts diabetes and cardiovascular risk with obesity. Clinical data show that estrogen signaling in males helps prevent adiposity and insulin resistance, which may be mediated through estrogen receptor-α (ERα). The tissues and pathways that mediate the benefits of estrogen signaling in males with ob...
متن کاملThe Effect of 6 Week Resistance Training Program on Foxo1 Expression in Liver Cells and Glucose and Insulin Levels in Type 2 Diabetic Rats
Background & objectives: Foxo1 is a transcription factor in insulin signaling in the liver. The function of Foxo1 is important in the ability of insulin to regulate hepatic glucose production and glucose homeostasis. The aim of this study was to determine the effect of resistance training program on Foxo1 expression in liver cells as well as glucose and insulin serum levels in male Wistar rat...
متن کاملThe Potential Protective Action of Vitamin D in Hepatic Insulin Resistance and Pancreatic Islet Dysfunction in Type 2 Diabetes Mellitus
Vitamin D deficiency (i.e., hypovitaminosis D) is associated with increased insulin resistance, impaired insulin secretion, and poorly controlled glucose homeostasis, and thus is correlated with the risk of metabolic diseases, including type 2 diabetes mellitus (T2DM). The liver plays key roles in glucose and lipid metabolism, and its dysregulation leads to abnormalities in hepatic glucose outp...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2017