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.