Cellular Pathogenesis of Liver Disease
Cirrhosis and liver cancer are prominent and increasing causes of morbidity and mortality world-wide. In most cases, both cirrhosis and hepatocellular carcinoma are the consequence of long-standing chronic inflammatory liver diseases such as viral hepatitis, alcohol-associated liver disease and non-alcoholic steatohepatitis. Our lab is focused on uncovering the mechanisms underlying inflammatory liver disease and understanding how this knowledge can be applied to the development of novel therapies. We have done extensive studies on HCV and alcohol-mediated liver injury investigating mechanisms leading to oxidative stress, mitochondrial injury pathways, viral-host interactions and innate immunity. Our lab focuses on cell biological approaches using cell culture systems, animal models and human samples but we have several clinical and translational studies involving patients with chronic hepatitis C, alcoholic hepatitis and hepatocellular carcinoma. Specific ongoing projects are:
Hepatic Macrophage Adaptation in Alochol-Associated Liver Disease
Liver macrophages including Kupffer cells and infiltrating macrophages serve to transmit injury inducing signals from gut-derived molecules to hepatocytes after alcohol exposure. Recent work from our lab and others shows that the liver macrophage population changes in an orchestrated fashion after alcohol exposure. Some of these changes are triggered by Kupffer cell apoptosis which can initiate an anti-inflammatory phenotype shift that protects the liver from continued alcohol exposure. Current projects in the lab are investigating FOXO3-dependent apoptosis as an inflammation regulator, using single cell RNA-seq studies of hepatic macrophages to understand adaptive and maladaptive changes in macrophage populations, and studying the process of immune response to alcohol in humans. This work uses both clinical specimens, transgenic mice and cell culture systems as experimental model systems.
Li Z, Weinman SA. Regulation of Hepatic Inflammation via Macrophage Cell Death. Semin Liver Dis. 2018 Nov;38(4):340-350. doi: 10.1055/s-0038-1670674. Epub 2018 Oct 24. Review.
Li Z, Zhao J, Zhang S, Weinman SA. FOXO3-dependent apoptosis limits alcohol-induced liver inflammation by promoting infiltrating macrophage differentiation. Cell Death Discov. 2018 Dec;4:16. doi: 10.1038/s41420-017-0020-7. eCollection 2018 Dec. PubMed PMID: 29531813; PubMed Central PMCID: PMC5841311.
Li Z, Zhao J, Tikhanovich I, Kuravi S, Helzberg J, Dorko K, Roberts B, Kumer S, Weinman SA. Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression. Cell Death Differ. 2016 Apr;23(4):583-95. doi: 10.1038/cdd.2015.125. Epub 2015 Oct 16. PubMed PMID: 26470730; PubMed Central PMCID: PMC4986632.
Mechanisms of Inflammatory Exosome Production and Cargo Loading
Inflammatory stimuli and diseases produce a burst of exosome production from affected cells that serve a cell-cell communication function that modulates host responses. These "inflammatory exosomes" have distinct protein and RNA content and are different in both quantity and composition from exosomes produced from the same cells prior to inflammation. Dr. Wozniak has been investigating how Hepatitis C infection alters trafficking and controls exosome secretion. Her work has discovered that caspase-1 cleaves the Rab protein trafficking adaptor RILP, rerouting cellular trafficking to suppress lysosomal fusion of autophagosomes, promote viral secretion and dramatically increase exosome production. These studies are now investigating the molecular details of these interactions, how they determine exosome cargo specificity and how they can be manipulated to improve the outcome of inflammatory liver disease.
Adams A, Weinman SA, Woniak AL. Caspase-1 regulates cellular trafficking via cleavage of the Rab7 adaptor protein RILP. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2619-2624. doi: 10.1016/j.bbrc.2018.08.013. Epub 2018 Aug 9. PMID: 30100068 PMCID: PMC6133719 [Available on 2019-09-18]
Wozniak AL, Long A, Jones-Jamtgaard KN, Weinman SA. Hepatitis C virus promotes virion secretion through cleavage of the Rab7 adaptor protein RILP. Proc Natl Acad Sci USA. 2016. Nov;113(44):12484-12489 doi: 10.1073/pnas.1607277113. PMID: 27791088 PMCID: PMC5098622