Therapy of experimental NASH and fibrosis with galectin inhibitors

PLoS One. 2013 Dec 18;8(12):e83481. doi: 10.1371/journal.pone.0083481. eCollection 2013.

Abstract

Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The results, in combination with previous experiments in toxin-induced fibrosis, suggest that these galectin-targeting drugs may have potential in human NASH with fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / metabolism
  • Carbohydrates / adverse effects
  • Carbohydrates / chemistry
  • Carbohydrates / pharmacology*
  • Carbohydrates / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Galectins / antagonists & inhibitors*
  • Hepatic Stellate Cells / drug effects
  • Kidney / drug effects
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Mice
  • Nitric Oxide Synthase Type II / metabolism
  • Non-alcoholic Fatty Liver Disease
  • Pregnancy
  • Time Factors

Substances

  • CD36 Antigens
  • Carbohydrates
  • Galectins
  • Nitric Oxide Synthase Type II

Grant support

Authors PGT and EZ are or have been employed by Galectin Therapeutics INC, a public company. Additionally, Galectin Therapeutics funded this work so the same authors have an affiliation to the commercial funders. Moreover, the company funders, beyond the employees involved in the study, had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.