Dissecting the Acid Ceramidase Pathway in Hepatic Fibrogenesis

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ABSTRACT Fibrosis is the final common pathway in chronic liver disease that leads to liver failure, and is characterized by an imbalance of extracellular matrix (ECM) deposition and remodeling. There are currently no FDA-approved therapies to target this endpoint of chronic liver disease. Moreover, there is a paucity of biomarkers that reflect disease-specific pathways in patients. Development of new therapeutics and biomarkers for patients with hepatic fibrosis is a critical unmet need. Our long-term goal is to develop antifibrotic therapies for the treatment of hepatic fibrosis and to develop biomarkers to define the patient populations that would benefit most from these therapies. Our prior studies discovered an antifibrotic target, the enzyme acid ceramidase (aCDase). Targeting aCDase ameliorates fibrosis by inhibiting YAP/TAZ, key effectors of the Hippo pathway, and promotes ECM remodeling. We developed a signature score of genes downregulated by ceramide, the Ceramide Responsiveness score (CRS), and demonstrated that the CRS is increased in patients with advanced fibrosis. Despite the fact that targeting aCDase in HSCs ameliorates activation in culture and ablating its expression prevents liver fibrosis in vivo, chronic ceramide accumulation may have untoward side effects. The overall objective of the proposal is to clarify the mechanisms by which ceramide regulates YAP/TAZ, ECM remodeling, and hepatic fibrosis. We also seek to validate the CRS as a pathway-specific biomarker in patients with hepatic fibrosis. The rationale for this project is that understanding the mechanisms of ceramide-mediated attenuation of HSC activation and hepatic fibrosis will offer a strong scientific framework to facilitate the development of antifibrotic therapeutics and biomarkers for patients. To achieve this objective, this proposal has three specific aims. In specific aim 1, we will determine the mechanism by which ceramide regulates Hippo signaling. In specific aim 2, we will characterize how ceramide regulates ECM remodeling. Specific aims 1 and 2 will be achieved by gain of function and loss of function techniques in vitro and testing HSC-specific knockout mice. In specific aim 3, we will analyze the correlation between the CRS, fibrosis stage, and fibrosis progression using deidentified human liver samples, and will identify clinical characteristics that correlate with the CRS. The mechanistic understanding to be gained from the successful completion of the proposed studies promises to reveal new targets for rational disease modification in hepatic fibrosis, a disease with limited treatment options available. Furthermore, by clarifying molecular mechanisms and defining a pathway-specific signature, our work will facilitate a personalized medicine approach for patients with hepatic fibrosis.