Alcohol-induced liver injury activates hepatic stellate cells (HSCs) resulting in hepatic fibrosis. Withdrawal from alcohol leads to regression of liver fibrosis and disappearance of HSCs/myofibroblasts. We have recently demonstrated that some activated HSCs apoptose, while other HSC inactivate and revert to a quiescent-like phenotype. The overall goals of this Project are to identify the molecular factors that may prevent HSC activation into myofibroblasts, or revert activated HSCs (aHSCs) into a quiescent-like state. Our central hypothesis is that genome wide epigenetic changes regulate HSC phenotype by activation (or suppression) of transcriptional activity in HSCs. We also hypothesize that activation of PPARg-target genes regulates the quiescent (gHSC) and inactivated (iHSC) phenotypes.
AIM1 A: We undertake two approaches to improve the model of intragastric ethanol infusion: optimization of the regiment of ethanol and high fat diet (HFD) administration, and utilization of """"""""humanized"""""""" transgenic mice expressing human CYP2E1 protein in Cyp2e1-null mice that make them more susceptible to alcohol-induced liver injury. We hypothesize that these mice also exhibit a defect in HSC inactivation during recovery from alcohol-induced liver fibrosis. """"""""AIM1B: We will use a translafional approach to explore whether our findings in mice apply to patients. Using flow cytometry, we will examine if HSC inactivation also occurs in patients. Inactivation of HSCs will be simulated in vitro by TGF-pi cessation, or in vivo by intrahepatic transplantation of human HSCs into Rag2-/- yc-/- mice. iHSCs will be identified by Vitamin A*aSMAGFAPlowPPARYhi phenotype.
AIM2 A: We will use Chip- Seq analysis to access the genome wide methylation and acetylation sites in qHSCs, aHSCs and iHSCs to identify motifs and transcription factors critical for HSC inactivation. Using primary HSC cultures, we will determine if siRNA knockdown or over-expression of these factors blocks HSC activation, or trigger HSC inactivation.
AIM2 B: We have demonstrated that PPARy is re-expressed in HSCs during inactivafion. To gain a greater insight into mechanisms of HSC inactivation, we will conduct a broad investigation of the epigenetic changes that regulate PPARy-target genes in distinct HSC phenotypes (qHSCs, aHSCs and IHSCs). We will test if functional inhibition of these genes compromises the qHSC and iHSC phenotypes. We anticipate that the results obtained in this study will identify specific factors that can revert aHSC into iHSCs and will give greater insight into mechanisms underlying HSC inactivation, validating potential therapeutic targets that can induce inactivation of already existing HSCs/myofibroblasts in fibrotic liver.
Alcoholic liver disease is a major cause of liver-related mortality and represents an enormous health care burden worldwide. The goal of this study is to determine the mechanism of activation of Hepatic Stellate cells/myofibroblasts, and identify the pathways of their inactivation into a quiescent-like state in alcoholic liver injury. Understanding of the mechanisms of myofibroblast inactivation is critical for the treatment of hepatic fibrosis, and will advance the field by providing novel targets for anti-fibrotic therapy.
|Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753|
|Zheng, Han; You, Yang; Hua, Meiyun et al. (2018) Chlorophyllin Modulates Gut Microbiota and Inhibits Intestinal Inflammation to Ameliorate Hepatic Fibrosis in Mice. Front Physiol 9:1671|
|Lew, Daniel; Wu, Bechien U; Pandol, Stephen J et al. (2018) Disease Course Differences in Acute Pancreatitis Based on Etiology Using the Pancreatitis Activity Scoring System. Pancreas 47:e40-e41|
|Ogawa, Tomohiro; Li, Yuchang; Lua, Ingrid et al. (2018) Isolation of a unique hepatic stellate cell population expressing integrin ?8 from embryonic mouse livers. Dev Dyn 247:867-881|
|Tripathi, Anupriya; Debelius, Justine; Brenner, David A et al. (2018) The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 15:397-411|
|Waldron, Richard T; Su, Hsin-Yuan; Piplani, Honit et al. (2018) Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model. Cell Mol Gastroenterol Hepatol 5:479-497|
|Waldron, Richard T; Lugea, Aurelia; Gulla, Aiste et al. (2018) Proteomic Identification of Novel Plasma Biomarkers and Pathobiologic Pathways in Alcoholic Acute Pancreatitis. Front Physiol 9:1215|
|Wu, Raymond; Murali, Ramachandran; Kabe, Yasuaki et al. (2018) Baicalein Targets GTPase-Mediated Autophagy to Eliminate Liver Tumor-Initiating Stem Cell-Like Cells Resistant to mTORC1 Inhibition. Hepatology 68:1726-1740|
|Buxbaum, James; Quezada, Michael; Chong, Bradford et al. (2018) The Pancreatitis Activity Scoring System predicts clinical outcomes in acute pancreatitis: findings from a prospective cohort study. Am J Gastroenterol 113:755-764|
|Zhao, Qinglan; Wei, Yi; Pandol, Stephen J et al. (2018) STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis. Gastroenterology 154:1822-1835.e2|
Showing the most recent 10 out of 415 publications