Bryan L. Copple
- Associate Professor, Department of Pharmacology and Toxicology
- Life Science
- 1355 Bogue St Room B403
- East Lansing MI 48824
- 517-884-6691
- copple@msu.edu
RESEARCH INTERESTS
Regulation of Inflammation in the Liver by Early Growth Response Factor-1:
Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This results in the accumulation of bile acids in the liver, hepatic inflammation, hepatocyte injury, and under chronic conditions, hepatic fibrosis. The pathogenesis of hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. Interestingly, inflammation associated with cholestasis occurs independently of tumor necrosis factor-a and interleukin-1, suggesting that this process is regulated by a novel, previously undescribed mechanism. Therefore, the overall goal of our research is to elucidate the mechanism by which cholestasis causes inflammation in the liver. Our studies indicate that the transcription factor, early growth response factor-1 (Egr-1), is critical for this process. Egr-1 is rapidly upregulated in hepatocytes during cholestasis. Upregulation of Egr-1 appears to be mediated directly by bile acids, since exposure of primary mouse hepatocytes to pathological concentrations of bile acids upregulates Egr-1. Our studies show further that upregulation of macrophage inflammatory protein-2, intercellular adhesion molecule-1, neutrophil accumulation, and hepatocyte injury are dramatically reduced in Egr-1 knockout mice with cholestasis. These results suggest that upregulation of Egr-1 in hepatocytes is vital for the development of neutrophil-dependent inflammatory liver injury, and as such, is a novel mechanism of inflammation in the liver. Furthermore, these studies indicate that Egr-1 provides the critical link between elevated concentrations of bile acids that occur during cholestasis and the production of proinflammatory mediators in liver. Elucidation of the molecular mechanism by which Egr-1 regulates inflammation would provide important insight into whether development of therapeutics that target Egr-1 would be effective for the treatment of hepatocyte injury in patients with cholestasis.
Role of Hypoxia-inducible Factors in the Development of Liver Fibrosis:
Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. Our studies have investigated the hypothesis that the transcription factor, hypoxia-inducible factor-1a (HIF-1a), is activated in the liver during chronic injury and regulates expression of profibrotic proteins. Hypoxia-inducible factors (HIFs) are a group of transcription factors that are rapidly activated in cells exposed to hypoxia. Once activated, these transcription factors translocate to the nucleus and regulate expression of genes involved in glycolysis, cell survival, proliferation, erythropoiesis and angiogenesis. To investigate the hypothesis that HIFs are important for fibrosis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1a protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1a is required for the development of fibrosis, Control and HIF-1a-deficient mice were subjected to BDL. Levels of type I collagen and a-smooth muscle actin mRNA and protein were increased in Control mice by 14 days after BDL. These levels were significantly reduced in HIF-1a-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1a promoted liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, fibroblast growth factor-2, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in Control mice subjected to BDL when compared to HIF-1a-deficient mice. Our studies demonstrate that HIF-1a is a critical regulator of profibrotic mediator production during the development of liver fibrosis.
EDUCATIONAL BACKGROUND
Morningside College, Iowa, B.S., 1991, Biology
University of Nebraska Medical Center, Ph.D., 1997, Pharmacology
AFFILIATED WEBSITES
https://phmtox.msu.edu/people/faculty/copple/