title: Adiponectin agonist ADP355 attenuates CCl4-induced liver fibrosis in mice.
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-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.
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, GA, United States of America.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, GA, United States of America.
authors.forename: Tekla
authors.initials: T
authors.lastname: Smith
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, GA, United States of America.
authors.forename: Khalidur
authors.initials: K
authors.lastname: Rahman
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, GA, United States of America.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Thorn
authors.affiliation: Emory University School of Medicine, Department of Medicine, Division of Digestive Diseases, Atlanta, GA, United States of America.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D052242:Adiponectin / Q000819:agonists* / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D052242:Adiponectin; D009842:Oligopeptides; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C000603754:asparaginyl-isoleucyl-prolyl-norvalyl-leucyl-tyrosyl-seryl-phenylalanyl-alanyl-serinamide; D003094:Collagen; D002251:Carbon Tetrachloride; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D053509:Matrix Metalloproteinase 13