Adiponectin agonist ADP355 attenuates CCl4-induced liver fibrosis in mice

• Published in: PloS one 2014-10, Vol.9 (10), p.e110405
• Main Authors: Kumar, Pradeep, Smith, Tekla, Rahman, Khalidur, Thorn, Natalie E, Anania, Frank A
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Adiponectin; Adiponectin - agonists; Adiponectin - metabolism; AKT protein; Alanine; Alanine transaminase; AMP-Activated Protein Kinases - metabolism; Animals; Arthritis; Aspartate aminotransferase; Attenuation; Blood circulation; Breast cancer; Carbon tetrachloride; Carbon Tetrachloride - adverse effects; Collagen; Collagen - metabolism; Connective tissue growth factor; Connective tissues; Disease Models, Animal; Fibrosis; Gene Expression; Global health; Gold; Histopathology; Hydroxyproline; Injection; Kinases; Liver; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Lysates; Male; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Medicine and Health Sciences; Metalloproteinase; Mice; Muscles; Nanoparticles; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Phosphorylation; Proteolysis - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Public health; Rodents; Smooth muscle; Stellate cells; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110405

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-α-smooth muscle actin (α-SMA), transforming growth factor-beta1 (TGF-β1), 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.