Hepatic fibrosis is a progressive condition resulting from a number of causes, including hepatitis, alcohol abuse, and nonalcoholic steatohepatitis, which can ultimately lead to cirrhosis and liver failure. Cirrhosis affects 900,000 persons, and the underlying causes (alcohol abuse and hepatitis infection) are more prevalent in the veteran population. There are currently few treatment options. Our previous studies showed that the hormone relaxin is effective in treating established hepatic fibrosis. Our recent data using mice lacking the relaxin receptor RXFP1 plays additional roles in hepatocyte regeneration and prevention of apoptosis. We have found evidence that relaxin triggers cross-talk between hepatic stellate cells and hepatocytes, by promoting the release of a soluble factor from stellate cells that stimulates hepatocyte proliferation. We have identified hepatocyte growth factor (HGF) as the likely factor affected. We also found that relaxin activation of RXFP1 activates the transcription factor PPAR? in an unconventional manner. Recently, new activators of PPAR? have been produced that promote insulin sensitivity, but do not cause the negative side effects of full agonist activators, making them attractive new antidiabetic treatments but their effect on fibrosis was unknown. Our preliminary data suggests that one of these selective PPAR? agonists, SR1664, reduces established hepatic fibrosis much more effectively than traditional PPAR? activators. Furthermore, the insulin-sensitizing properties of SR1664 provide the potential for treatment not only of the fibrosis itself, but also the metabolic dysfunction associated with alcoholic and nonalcoholic fatty liver disease. Despite these findings, little is known about the role of relaxinin liver regeneration and apoptosis in other models of liver injury, how relaxin acts to regulate the PPAR? pathway, or the efficacy of selective PPAR? activation in fibrotic and metabolic liver disease. Our central hypothesis is that relaxin and selective PPAR? activation can reduce fibrosis and promote hepatocyte regeneration through HGF. To test this hypothesis, we propose three Specific Aims: 1. Establish the role of relaxin signaling in hepatic injury and repair 2. Determine the mechanism for the HSC-hepatocyte interaction regulated by relaxin. 3. Determine the efficacy of selective activation of PPAR? in models of fibrotic and metabolic liver disease.
In Aim 1, total and tissue-specific RXFP1-null mice will be subject to models of early and late liver injury, and the degree of damage and liver regeneration will be compared with wild-type mice. Altered signaling pathways and cell cycle proteins will be defined.
In Aim 2, liver cells from wild-type and knockout mice will be used to define the relaxin-stimulated soluble factors released by HSC to stimulate hepatocyte proliferation and repress apoptosis. In vivo, HGF treatment will be used to rescue the defect in liver repair after injury.
In Aim 3, the PPAR? selective activator SR1664 will be used to treat experimental models of fibrotic and metabolic liver disease. Tissue-specific PPAR?-null mice will be used to identify the respective roles of liver cell populations on the effect of SR1664 and relaxin. Taken together, successful completion of these Aims will provide critical new insights into potential new approaches to the treatment not only of hepatic fibrosis, but also metabolic liver diseases as well. This would provide the potential expand the role of relaxin beyond fibrosis to the spectrum of liver diseases and comorbidities, which is a major issue not only in the population at-large, but particularly in the veteran population, in which liver disease and comorbidities are more prevalent.
Potential Impact on Veterans Health Care: Cirrhosis affects 900,000 people and is the 12th largest cause of death, with 36,000 cirrhosis-related deaths annually in the U.S. The major causes of cirrhosis (hepatitis C virus and alcohol abuse) are significantly more prevalent in Veterans than in the general population. Furthermore, another major risk factor for cirrhosis, fatty liver disease, is a rapidly growing problem with the increased obesity and diabetes in the Veteran population. Therefore, treatment of cirrhosis and its underlying causes is an area of particular concern in the VA Health Care System. Treatment options are currently limited to removal of the cause of the injury, which is not always possible or effective, or transplantation. The research proposed in this application may lead to targeted therapeutic strategies for the treatment of liver disease, a major health concern in the Veteran population.
| Samuel, C S; Royce, S G; Hewitson, T D et al. (2017) Anti-fibrotic actions of relaxin. Br J Pharmacol 174:962-976 |
| McVicker, Benita L; Bennett, Robert G (2017) Novel Anti-fibrotic Therapies. Front Pharmacol 8:318 |
| Bennett, Robert G; Simpson, Ronda L; Hamel, Frederick G (2017) Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis. World J Gastroenterol 23:3999-4006 |
| Singh, Sudhir; Simpson, Ronda L; Bennett, Robert G (2015) Relaxin activates peroxisome proliferator-activated receptor ? (PPAR?) through a pathway involving PPAR? coactivator 1? (PGC1?). J Biol Chem 290:950-9 |
