For the past 20 years Dr. Laura Schrum, research group director, has been dedicated to investigating the intricate cellular and molecular mechanisms of liver fibrosis. Hepatic fibrosis/cirrhosis is an exacerbation of the generic wound-healing response resulting in excess deposition of extracellular matrix (ECM) proteins (e.g. collagen) by activated hepatic stellate cells (HSCs). Chronic liver disease and cirrhosis is the 12th leading cause of death in the US, and total costs in the US have been estimated at $10 billion/yr (direct and indirect costs). Fibrosis/cirrhosis can be initiated by many factors including chronic alcoholism and exposure to Hepatitis B and C viruses (HBV and HCV). Furthermore, nonalcoholic fatty liver disease (NAFLD), a consequence of obesity, is currently the leading cause of chronic liver disease affecting approximately 30 percent of the US population. NAFLD can progress to nonalcoholic steatohepatitis (NASH) with further advancement to fibrosis, cirrhosis and ultimately, hepatocellular carcinoma (HCC), the 3rd leading cause of cancer death worldwide. As HSC activation is a pivotal event in initiation and progression of fibrosis/cirrhosis, interfering with HSC activation is an obvious and attractive therapeutic target to impede liver disease advancement. Currently there are no established FDA-approved treatments for fibrosis/cirrhosis, and liver transplant remains the only cure for cirrhosis. Therefore, establishing treatments for fibrosis/cirrhosis will decrease yearly deaths and US economic burden.
During development of fibrosis there are critical changes in microRNAs (miR), small non-coding RNAs, which regulate wound-healing transcripts. Therapeutic modulation of miRs by inhibiting or increasing miR expression holds great promise to restore delicate genetic programs vital to normal organ function. In the Liver Pathobiology Laboratory, researchers have identified specific miRs as important mediators for hepatic fibrosis development. Scientists demonstrated that these miRs are decreased in fibrotic liver, promoting profibrogenic signaling in the HSC. To demonstrate the clinical relevance, similar results have been concluded in human livers. These studies also revealed increased levels of specific miRs in serum of fibrotic patients compared to tissue suggesting these miRs are released from fibrotic livers into circulation. This increase in specific serum miRs can be employed as a non-invasive diagnostic marker for fibrosis. Studies are currently in progress to test these miRs as a therapy for fibrosis in animal models. Overall, these studies propose that this concept may serve as a therapy and non-invasive diagnostic biomarker for liver fibrosis.
For fibrosis to initiate, HSCs undergo an activation/transdifferentiation process, and we have identified nuclear receptor Rev-erb as a key regulator in this process. Studies showed suppressive effects on HSC activation when cells were exposed to a Rev-erb ligand/agonist, resulting in a decreased fibrogenic response (i.e. fibrotic gene expression). This data in addition with other data suggests a functional role of Rev-erb in maintaining/promoting the non-fibrogenic HSC phenotype while suppressing fibrogenic gene expression. Studies are currently underway to test a Rev-erb agonist in a fibrotic animal model with the expectation that Rev-erb can serve as a therapeutic target for the treatment of hepatic fibrosis and related pathologies.
Although cirrhosis is currently the greatest risk factor in the development of HCC, obesity is also an independent risk factor. The majority of HCC cases (80-90 percent) develop within a microenvironment characterized by persistent injury, inflammation and fibrosis/cirrhosis. HSC activation is critical for the initiation and progression of NAFLD to fibrosis/cirrhosis, thus making the HSC an attractive therapeutic target to prevent liver disease advancement to HCC. We recently identified nuclear transcriptional repressor Rev-erba as a novel regulator of HSC activation and the fibrogenic response. Rev-erb agonists, which increase transcriptional repressor activity of Rev-erba, were shown to reduce fibrogenic events including decreased expression of ECM proteins in activated HSCs (i.e. tenascin-C, TnC), while promoting the adipogenic/quiescent phenotype. TnC is an endogenous activator of Toll-like receptor 4 (TLR4) signaling which promotes epithelial-mesenchymal transition and the development of HCC. In liver injury, activated HSCs are the primary cellular source of TnC which can be blocked by Rev-erb agonists. Therefore, we are testing that upon liver injury activated HSCs increase secretion of TnC, an event regulated by Rev-erba, which signals through TLR4, promoting hepatocyte transformation and development of obesity-induced HCC.
Overall, the Liver Pathobiology Laboratory, located on the campus of Carolinas Medical Center, will continue their efforts to bring bench research to the bedside to unfold cellular and molecular mechanisms of several liver diseases with the expectation of identifying biomarkers and developing novel therapeutic strategies. These research endeavors are aimed at providing improved and high quality patient care and superior personalized medicine.
Email: Laura W. Schrum