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Browsing by Author "Maiers, Jessica L."
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Item ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets(Frontiers, 2022-01) Duwaerts, Caroline C.; Maiers, Jessica L.; Medicine, School of MedicineThe endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.Item Melatonin-MT1 Signaling Axis Ameliorates the Phenotypes of Primary Sclerosing Cholangitis(2023-03) Ceci, Ludovica; Alpini, Gianfranco; Francis, Heather; Ekser, Burcin; Dong, Charlie X.; Maiers, Jessica L.Background: Primary Sclerosing Cholangitis (PSC) is characterized by hepatic fibrosis and portal inflammation. Melatonin is synthesized by arylalkylamine N-acetyltransferase (AANAT) in cholangiocytes. We found that: (i) the MT1 receptor is primarily expressed in cholangiocytes; (ii) melatonin reduces biliary proliferation via MT1 receptor signaling; and (iii) melatonin treatment for 1 wk decreases ductular reaction (DR) and liver fibrosis in cholestatic rats by downregulation of MT1 and clock genes. Melatonin administration to male Mdr2-/- mice (PSC model) reduces angiogenesis and portal inflammation via decreased miR-200b. Downregulation of maspin triggers angiogenesis during tumorigenesis by interaction with glutathione S-transferase (GST). We aimed to evaluate the effects of long-term melatonin treatment and MT1 signaling on PSC phenotypes in Mdr2-/- mice. Methods: Male FVB/NJ and Mdr2-/- mice had access ad libitum to drinking water with/without melatonin for 3 months. Immortilized-SV40-cholangiocytes isolated from human liver samples (control and PSC) were treated with melatonin (10-3 mol/L) for 24 hr. Male C3H-Hej (WT for MT1-/-), FVB/NJ (WT for Mdr2-/-), MT1-/-, Mdr2-/- mice and MT1-/-/Mdr2-/- mice were euthanized at 12 wk. We analyzed liver damage, PSC phenotypes, angiogenesis and AANAT, melatonin receptors and clock genes by immunohistochemistry, immunofluorescence, ELISA and western blots in liver samples and isolated cholangiocytes. Melatonin signaling was evaluated in human control and PSC samples. Results: Long-term melatonin treatment and inhibition of MT1 receptor ameliorates cholestatic liver phenotypes in Mdr2-/-mice by decreasing the immunoreactivity of melatonin enzymes and clock genes. GST activity and maspin expression decreased in Mdr2-/- mice and human PSC samples compared to controls; the phenotypes were reversed by melatonin. Conclusion: Chronic melatonin treatment improves liver histology and restores biliary circadian rhythm by interaction with MT1. Suppression of MT1 ameliorates biliary/liver phenotypes through changes in clock genes and melatonin enzymes. Restoration of the circadian rhythm by modulation of melatonin/MT1 signaling may be key for PSC management.Item Traf2 and NCK Interacting Kinase Is a Critical Regulator of Procollagen I Trafficking and Hepatic Fibrogenesis in Mice(Wiley, 2022-03) Buchl, Samuel C.; Hanquier, Zachary; Haak, Andrew J.; Thomason, Yvonne M.; Huebert, Robert C.; Shah, Vijay H.; Maiers, Jessica L.; Medicine, School of MedicineHepatic fibrosis is driven by deposition of matrix proteins following liver injury. Hepatic stellate cells (HSCs) drive fibrogenesis, producing matrix proteins, including procollagen I, which matures into collagen I following secretion. Disrupting intracellular procollagen processing and trafficking causes endoplasmic reticulum stress and stress-induced HSC apoptosis and thus is an attractive antifibrotic strategy. We designed an immunofluorescence-based small interfering RNA (siRNA) screen to identify procollagen I trafficking regulators, hypothesizing that these proteins could serve as antifibrotic targets. A targeted siRNA screen was performed using immunofluorescence to detect changes in intracellular procollagen I. Tumor necrosis factor receptor associated factor 2 and noncatalytic region of tyrosine kinase-interacting kinase (TNIK) was identified and interrogated in vitro and in vivo using the TNIK kinase inhibitor NCB-0846 or RNA interference-mediated knockdown. Our siRNA screen identified nine genes whose knockdown promoted procollagen I retention, including the serine/threonine kinase TNIK. Genetic deletion or pharmacologic inhibition of TNIK through the small molecule inhibitor NCB-0846 disrupted procollagen I trafficking and secretion without impacting procollagen I expression. To investigate the role of TNIK in liver fibrogenesis, we analyzed human and murine livers, finding elevated TNIK expression in human cirrhotic livers and increased TNIK expression and kinase activity in both fibrotic mouse livers and activated primary human HSCs. Finally, we tested whether inhibition of TNIK kinase activity could limit fibrogenesis in vivo. Mice receiving NCB-0846 displayed reduced CCl4-induced fibrogenesis compared to CCl4 alone, although α-smooth muscle actin levels were unaltered. Conclusions: Our siRNA screen effectively identified TNIK as a key kinase involved in procollagen I trafficking in vitro and hepatic fibrogenesis in vivo.Item Transcriptomic Analysis Reveals the Messenger RNAs Responsible for the Progression of Alcoholic Cirrhosis(Wolters Kluwer, 2022) Yang, Zhihong; Han, Sen; Zhang, Ting; Kusumanchi, Praveen; Huda, Nazmul; Tyler, Kelsey; Chandler, Kristina; Skill, Nicholas J.; Tu, Wanzhu; Shan, Mu; Jiang, Yanchao; Maiers, Jessica L.; Perez, Kristina; Ma, Jing; Liangpunsakul, Suthat; Medicine, School of MedicineAlcohol-associated liver disease is the leading cause of chronic liver disease. We hypothesized that the expression of specific coding genes is critical for the progression of alcoholic cirrhosis (AC) from compensated to decompensated states. For the discovery phase, we performed RNA sequencing analysis of 16 peripheral blood RNA samples, 4 healthy controls (HCs) and 12 patients with AC. The DEGs from the discovery cohort were validated by quantitative polymerase chain reaction in a separate cohort of 17 HCs and 48 patients with AC (17 Child-Pugh A, 16 Child-Pugh B, and 15 Child-Pugh C). We observed that the numbers of differentially expressed messenger RNAs (mRNAs) were more pronounced with worsening disease severity. Pathway analysis for differentially expressed genes for patients with Child-Pugh A demonstrated genes involved innate immune responses; those in Child-Pugh B belonged to genes related to oxidation and alternative splicing; those in Child-Pugh C related to methylation, acetylation, and alternative splicing. We found significant differences in the expression of heme oxygenase 1 (HMOX1) and ribonucleoprotein, PTB binding 1 (RAVER1) in peripheral blood of those who died during the follow-up when compared to those who survived. Conclusion: Unique mRNAs that may implicate disease progression in patients with AC were identified by using a transcriptomic approach. Future studies to confirm our results are needed, and comprehensive mechanistic studies on the implications of these genes in AC pathogenesis and progression should be further explored.