Dr. Reza Zarnegar published a manuscript in Cellular and Molecular Gastroenterology and Hepatology, entitled, “A novel humanized model of NASH and its treatment with META4 a potent agonist of MET.” PLRC members, Dr. Andrew Duncan and Dr. Marie DeFrances, and junior faculty, Dr. Evan Delgado, also contributed to this paper.
Background & aims: Non-alcoholic fatty liver disease (NAFLD) is a frequent cause of hepatic dysfunction and is now a global epidemic. This ailment can progress to an advanced form called NASH (non-alcoholic steatohepatitis) and end-stage liver disease. Currently, the molecular basis of NASH pathogenesis is poorly understood, and no effective therapies exist to treat NASH. These shortcomings are due to the paucity of experimental NASH models directly relevant to humans.
Methods: We used chimeric mice with humanized liver to investigate NAFLD in a relevant model. We carried out histologic, biochemical and molecular approaches including RNA-Seq. For comparison we used side-by-side human NASH samples.
Results: Herein, we describe a “humanized” model of NASH using transplantation of human hepatocytes into FAH (fumarylacetoacetate hydrolase) deficient mice. Once fed a high fat diet, these mice develop NAFLD faithfully recapitulating human NASH at the histologic, cellular, biochemical and molecular levels. Our RNA-Seq analyses uncovered that a variety of important signaling pathways that govern liver homeostasis are profoundly deregulated in both humanized and human NASH livers. Notably, we made the novel discovery that HGF (Hepatocyte Growth Factor) function is compromised in human and humanized NASH at several levels including a significant increase in the expression of the HGF antagonists known as NK1/NK2 and marked decrease in HGF activator (HGFAC). Based on these observations, we generated a potent, human specific and stable agonist of human MET that we have named META4 (Metaphor) and used it in the humanized NASH model to restore HGF function.
Conclusions: Our studies revealed that the humanized NASH model recapitulates human NASH and uncovered that HGF-MET function is impaired in this disease. We show that restoring HGF-MET function by META4 therapy ameliorates NASH and reinstates normal liver function in the humanized NASH model. Our results show that the HGF-MET signaling pathway is a dominant regulator of hepatic homeostasis.