The Dipeptide Pro-Gly Promotes IGF-1 Expression and Secretion in HepG2 and Female Mice via PepT1-JAK2/STAT5 Pathway.

Jingren Xu,Gang Shu,Mengyuan Zhang,Xiaojuan Wan,Xiaotong Zhu,Ping Gao,Songbo Wang,Fenglin Zhang,Qingyan Jiang,Lina Wang,Tao Wang

doi:10.3389/fendo.2018.00424

Abstract

It has been shown that IGF-1 secretion is influenced by dietary protein or amino acid. However, whether the dipeptides elicit regulatory effects on IGF-1 secretion remains largely unclear. Thus, this study aimed to investigate the effects of the dipeptide Pro-Gly on IGF-1 expression and secretion in HepG2 cells and mice, and explore the underlying mechanisms. The in vitro results indicated that Pro-Gly, but not Pro plus Gly, promoted the expression and secretion of IGF-1 in HepG2. Meanwhile, the expression of the peptide transporter 1 (PepT1) was elevated by Pro-Gly, whereas knockdown of PepT1 with siRNA eliminated the increase of IGF-1 expression induced by Pro-Gly. In addition, Pro-Gly activated JAK2/STAT5 signaling pathway in a PepT1-dependent manner. Furthermore, Pro-Gly enhanced the interaction between JAK2 and STAT5, and the translocation of phospho-STAT5 to nuclei. Moreover, inhibition of JAK2/STAT5 blocked the promotive effect of Pro-Gly on IGF-1 expression and secretion. In agreement with the in vitro results, the in vivo findings demonstrated that Pro-Gly, but not Pro plus Gly, stimulated the expression and secretion of IGF-1 and activated JAK2/STAT5 signaling pathway in the liver of mice injected with Pro-Gly or Pro+Gly acutely or chronically. Besides, acute injection of JAK2/STAT5 inhibitor abolished the elevation of IGF-1 expression and secretion induced by Pro-Gly in mice. Collectively, these findings suggested that the dipeptide Pro-Gly promoted IGF-1 expression and secretion in HepG2 cells and mice by activating JAK2/STAT5 signaling pathway through PepT1. These data provided new insights to the regulation of IGF-1 expression and secretion by the dipeptides.

Highlights

Insulin-like growth factor-1 (IGF-1) is a 70-amino acid hormone with effects on almost every tissue and organ [1,2,3], playing an essential role in growth [4, 5], metabolism [6, 7], and survival [8, 9]
Results from Co-IP experiments showed that the interaction between Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) was enhanced by Pro-Gly treatment in HepG2 cells (Figure 4C)
Pro-Gly treatment increased phospho-STAT5 translocation to nuclei in HepG2 cells (Figure 4D and Figure S3 in Data Sheet 1). These findings further suggested that activation of the JAK2/STAT5 signaling pathway might contribute to Pro-Gly-increased IGF-1 expression and secretion in HepG2 cells through peptide transporter 1 (PepT1)

Summary

Introduction

Insulin-like growth factor-1 (IGF-1) is a 70-amino acid hormone with effects on almost every tissue and organ [1,2,3], playing an essential role in growth [4, 5], metabolism [6, 7], and survival [8, 9]. JAK2 recruits and phosphorylates signal transducer and activator of transcription (STAT) 5, leading to its dimerization and translocation to the nucleus, where it binds to specific regulatory elements of IGF-1 and stimulates the production of hepatic IGF-1 [11,12,13]. It has been demonstrated that the dipeptides are actively transported across membranes as an efficient route for dietary protein absorption via a proton-coupled peptide transporter 1 (PepT1) [20], which is present in the various tissues such as intestine [21], kidney [22], pancreas, bile duct and liver [23]. The dipeptide Phe-Cys exerts antioxidant function in hepatocytes [26], while the dipeptides Gly-Gly and Arg-Arg have anti-inflammatory effects via PepT1 [27, 28]. The dipeptide Trp-His has been shown to elicit anti-atherosclerotic effects in rats [29], and Hyp-Gly promotes C2C12 myoblast differentiation and myotube hypertrophy [30]

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