Adiponectin Agonist ADP355 Attenuates CCl4-Induced Liver Fibrosis in Mice

• Type of Material: Article
• Authors: Pradeep Kumar, Emory University; Tekla Smith, Emory University; Khalidur Rahman, Emory University; Natalie E. Thorn, Emory University; Frank A Anania, Emory University
• Language: English
• Date: 2014-10-13
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Kumar et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0110405
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 10
• Start Page: e110405
• End Page: e110405
• Grant/Funding Information: The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The study was supported by funding from US PHS National Institutes of Health grants DK R01062092 and PHS VA I01BX001746.
• Keywords: Multidisciplinary Sciences; HEPATOCELLULAR-CARCINOMA; TISSUE GROWTH-FACTOR; GOLD NANOPARTICLES; Science & Technology - Other Topics; MECHANISMS; NITRIC-OXIDE; FIBROGENESIS; RATS; Science & Technology; LEPTIN; ACTIVATION; HEPATIC STELLATE CELLS
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Liver fibrosis is a growing global health problem characterized by excess deposition of fibrillar collagen, and activation of hepatic stellate cells (HSCs). Adiponectin is known to possess anti-fibrotic properties; however a high physiological concentration and multiple forms circulating in blood prohibit clinical use. Recently, an adiponectin-like small synthetic peptide agonist (ADP355: H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2) was synthesized for the treatment of murine breast cancer. The present study was designed to evaluate the efficacy of ADP355 as an anti-fibrotic agent in the in vivo carbon tetrachloride (CCl4)-induced liver fibrosis model. Liver fibrosis was induced in eight-week old male C57BL/6J mice by CCl4-gavage every other day for four weeks before injection of a nanoparticle-conjugated with ADP355 (nano-ADP355). Control gold nanoparticles and nano-ADP355 were administered by intraperitoneal injection for two weeks along with CCl4- gavage. All mice were sacrificed after 6 weeks, and serum and liver tissue were collected for biochemical, histopathologic and molecular analyses. Biochemical studies suggested ADP355 treatment attenuates liver fibrosis, determined by reduction of serum aspartate aminotransferase (AST), alanine aminotransferase ALT) and hydroxyproline. Histopathology revealed chronic CCl4-treatment results in significant fibrosis, while ADP355 treatment induced significantly reversed fibrosis. Key markers for fibrogenesis-a-smooth muscle actin (a-SMA), transforming growth factor-beta1 (TGF-b1), connective tissue growth factor (CTGF), and the tissue inhibitor of metalloproteinase I (TIMP1) were also markedly attenuated. Conversely, liver lysates from ADP355 treated mice increased phosphorylation of both endothelial nitric oxide synthase (eNOS) and AMPK while AKT phosphorylation was diminished. These findings suggest ADP355 is a potent anti-fibrotic agent that can be an effective intervention against liver fibrosis.