Adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activities in thioacetamide-induced liver injury.

Huafeng Wang,Zhi Yao,Fei Gao,Xixi Cheng,Zha La Gahu,Yurong Da,Daiqing Li,Huan Zhang,Rongxin Zhang,Dan Wang,Zimu Zhang,Biao Huang,Zhenyi Xue,Aimin Xu

doi:10.1038/srep19445

Abstract

Adiponectin is an adipocyte-derived circulating protein with beneficial effects on injured livers. Adiponectin-deficient (adipo(−/−)) mice develop enhanced liver fibrosis, suggesting that adiponectin could be a therapeutic target for liver injury. In the present study, we investigated the protective role of ADP355, an adiponectin-based active short peptide, in thioacetamide (TAA)-induced acute injury and chronic liver fibrosis in mice. ADP355 remarkably reduced TAA-induced necroinflammation and liver fibrosis. ADP355 treatment increased liver glycogen, decreased serum alanine transaminase and alkaline phosphatase activity, and promoted body weight gain, hyper-proliferation and hypo-apoptosis. In addition, ADP355 administration suppressed the TAA-induced activation of hepatic stellate cells and macrophages in the liver. These were associated with the inactivation of TGF-β1/SMAD2 signaling and the promotion of AMPK and STAT3 signaling. Sensitivity of adipo(−/−) mice to chronic liver injury was decreased with ADP355. In conclusion, ADP355 could mimic adiponectin’s action and may be suitable for the preclinical or clinical therapy of chronic liver injury.

Highlights

Numerous studies have analyzed the roles of adipokines in the hepatic wound healing process, identifying novel roles as modulators of liver pathophysiology[1]
ADP355 was used as a positive control for screening adiponectin receptor agonists in a high-throughput assay based on a fluorescence polarization, and several compounds were identified as potential adiponectin receptor agonists[9]
Liver fibrosis is a characteristic of every chronic liver disease[10]

Summary

Introduction

Numerous studies have analyzed the roles of adipokines in the hepatic wound healing process, identifying novel roles as modulators of liver pathophysiology[1]. A novel adiponectin-based short peptide, ADP355, was generated using a panel of 66 overlapping 10-amino-acid-long peptides covering the entire adiponectin globular domain (residues 105–254)[7]. As reported, it showed anti-tumor effects on several adiponectin receptor-positive cancer cell lines in a dose-dependent manner and on the growth of orthotopic human breast cancer xenografts by 31% in vivo[7]. ADP355 was reported to offset the detrimental effects of HIV protease inhibitor (PI)-induced metabolic dysfunction in experimental animal models[8] These results showed that ADP355 administration partially reversed PI-induced loss of subcutaneous adipose tissue; attenuated PI-induced hyperinsulinemia, hypertriglyceridemia, and hypoadiponectinemia; and prevented PI-induced cognitive impairment and brain injury[8]. We established the experimental liver injury models with TAA, and the administration of ADP355 was performed to examine whether ADP355 functions with adiponectin-like action against inflammation and liver fibrosis and attenuated the enhancement of liver fibrosis in adipo(− /− ) mice

Methods

Results

Conclusion