Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced steatohepatitis (SAH), cirrhosis, and liver cancer. Effective therapies are lacking because the mechanisms driving the pathogenesis and progression of these conditions are unclear. This research program has evaluated the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors, but then silencing these programs so that the liver matures. Thus, we will next evaluate the hypothesis that alcohol-related liver diseases progress because mechanisms controlling when fetal programs are switched on and off in adult liver cells are dysregulated. We have evidence that liver failure in human SAH results from over-activation of fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not suppressed sufficiently for injured livers to regenerate. To define tractable mechanisms that control adult-fetal ?switching? in hepatocytes of alcohol-injured livers we will leverage our recently published data which show that the RNA binding protein ESRP2 is critically important for switching on the adult program in developing livers, and that over-expressing ESRP2 blocks adult liver regeneration. ESRP2 regulates the splicing of ~20% of hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control hepatocyte proliferation and differentiation.
Aims 1 and 2 will use ESRP2-knockout and over-expressing mice to determine how manipulating fetal RNA splicing programs impacts progression of alcohol-induced liver injury.
In Aim 3 next generation sequencing and computational analysis will identify a conserved repertoire of RNA binding proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury in both mice and humans, thereby revealing novel therapeutic targets to improve recovery from ALD.
Patients already have alcoholic liver disease (ALD) when they present for medical care. Thus, a primary goal of treatment is to expedite liver repair. Successful repair regenerates mature liver cells without causing liver failure, cirrhosis, or cancer. Our research is significant because it is revealing how to optimize liver repair and thus, recovery from ALD.
| Oh, Seh-Hoon; Swiderska-Syn, Marzena; Jewell, Mark L et al. (2018) Liver regeneration requires Yap1-TGF?-dependent epithelial-mesenchymal transition in hepatocytes. J Hepatol 69:359-367 |
| Verdelho Machado, Mariana; Diehl, Anna Mae (2018) The hedgehog pathway in nonalcoholic fatty liver disease. Crit Rev Biochem Mol Biol 53:264-278 |
| Chen, Jiamei; Chen, Long; Zern, Mark A et al. (2017) The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 37:1260-1271 |
| Machado, Mariana Verdelho; Diehl, Anna Mae (2016) Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology 150:1769-77 |
| Michelotti, Gregory; Jiang, Xiaoyin; Sosa, Julie Ann et al. (2015) LGR5 is associated with tumor aggressiveness in papillary thyroid cancer. Oncotarget 6:34549-60 |
| Chan, Isaac S; Guy, Cynthia D; Machado, Mariana V et al. (2014) Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res 38:787-800 |
| Rangwala, Fatima; Omenetti, Alessia; Diehl, Anna Mae (2011) Cancer stem cells: repair gone awry? J Oncol 2011:465343 |
| Philips, George M; Chan, Isaac S; Swiderska, Marzena et al. (2011) Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS One 6:e23943 |
| Rangwala, Fatima; Guy, Cynthia D; Lu, Jiuyi et al. (2011) Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol 224:401-10 |
| Mao, Hua; Diehl, Anna Mae; Li, Yin-Xiong (2009) Sonic hedgehog ligand partners with caveolin-1 for intracellular transport. Lab Invest 89:290-300 |
Showing the most recent 10 out of 43 publications
