Browsing by Subject "Liver"

Now showing 1 - 10 of 130
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    A computational model of liver tissue damage and repair
    (Public Library of Science, 2020-12-21) Adhyapok, Priyom; Fu, Xiao; Sluka, James P.; Clendenon, Sherry G.; Sluka, Victoria D.; Wang, Zemin; Dunn, Kenneth; Klaunig, James E.; Glazier, James A.; Medicine, School of Medicine
    Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (α), conversion of healthy to stressed cells (β) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/β (fast proliferation), combined with a large γ/β (slow death) have the lowest probabilities of tissue survival. At large α/β, tissue fate can be described by a critical γ/β* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.
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    Abnormal liver tests are not sufficient for diagnosis of hepatic graft‐versus‐host disease in critically ill patients
    (Wolters Kluwer, 2022) Yang, Alexander H.; Han, Mai Ai Thanda; Samala, Niharika; Rizvi, Bisharah S.; Marchalik, Rachel; Etzion, Ohad; Wright, Elizabeth C.; Patel, Ruchi; Khan, Vinshi; Kapuria, Devika; Venkat, Vikramaditya Samala; Kleiner, David E.; Koh, Christopher; Kanakry, Jennifer A.; Kanakry, Christopher G.; Pavletic, Steven; Williams, Kirsten M.; Heller, Theo; Medicine, School of Medicine
    Hepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = -0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period -30 (days 30 to 16 before death) to period -15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.
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    Adult Diffuse Hepatic Hemangiomatosis: A Rare Cause of Dilated Cardiomyopathy and Sudden Cardiac Arrest
    (Springer, Part of Springer Science+Business Media, 2014-01) Supakul, Rodjawan; Vakili, Saeed T.; Liangpunsakul, Suthat; Department of Medicine, IU School of Medicine
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    Advancing the Metabolic Dysfunction-Associated Steatotic Liver Disease Proteome: A Post-Translational Outlook
    (MDPI, 2025-03-12) Chowdhury, Kushan; Das, Debajyoti; Huang, Menghao; Biochemistry and Molecular Biology, School of Medicine
    Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.
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    Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver
    (Wiley, 2015-08) Burgess, Kimberly S.; Philips, Santosh; Benson, Eric A.; Desta, Zeruesenay; Gaedigk, Andrea; Gaedigk, Roger; Segar, Matthew W.; Liu, Yunlong; Skaar, Todd C.; Department of Pharmacology and Toxicology, IU School of Medicine
    Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.
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    Aging exaggerates acute-on-chronic alcohol-induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1-C/EBPα-miRNA-223 axis
    (Wolters Kluwer, 2022) Ren, Ruixue; He, Yong; Ding, Dong; Cui, Aoyuan; Bao, Huarui; Ma, Jing; Hou, Xin; Li, Yu; Feng, Dechun; Li, Xiaoling; Liangpunsakul, Suthat; Gao, Bin; Wang, Hua; Medicine, School of Medicine
    Background and aims: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses. Approach and results: Young and aged myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR-223 expression were down-regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and down-regulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, down-regulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients. Conclusions: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans through the down-regulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.
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    Alcohol and medication interactions
    (U.S. National Institute on Alcohol Abuse and Alcoholism, 1999) Weathermon, Ron; Crabb, David W.; Medicine, School of Medicine
    Many medications can interact with alcohol, thereby altering the metabolism or effects of alcohol and/or the medication. Some of these interactions can occur even at moderate drinking levels and result in adverse health effects for the drinker. Two types of alcohol-medication interactions exist: (1) pharmacokinetic interactions, in which alcohol interferes with the metabolism of the medication, and (2) pharmacodynamic interactions, in which alcohol enhances the effects of the medication, particularly in the central nervous system (e.g., sedation). Pharmacokinetic interactions generally occur in the liver, where both alcohol and many medications are metabolized, frequently by the same enzymes. Numerous classes of prescription medications can interact with alcohol, including antibiotics, antidepressants, antihistamines, barbiturates, benzodiazepines, histamine H2 receptor antagonists, muscle relaxants, nonnarcotic pain medications and anti-inflammatory agents, opioids, and warfarin. In addition, many over-the-counter and herbal medications can cause negative effects when taken with alcohol.
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    Aspects of regulation of hepatic metabolism
    (1979) Ochs, Raymon
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    Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
    (Nature Research, 2018-11-23) Lee, Youngmin A.; Noon, Luke A.; Akat, Kemal M.; Ybanez, Maria D.; Lee, Ting-Fang; Berres, Marie-Luise; Fujiwara, Naoto; Goossens, Nicolas; Chou, Hsin-I; Parvin-Nejad, Fatemeh P.; Khambu, Bilon; Kramer, Elisabeth G.M.; Gordon, Ronald; Pfleger, Cathie; Germain, Doris; John, Gareth R.; Campbell, Kirk N.; Yue, Zhenyu; Yin, Xiao-Ming; Cuervo, Ana Maria; Czaja, Mark J.; Fiel, M. Isabel; Hoshida, Yujin; Friedman, Scott L.; Pathology and Laboratory Medicine, School of Medicine
    Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.