scholarly journals Liver Cell Death: Update on Apoptosis

2003 ◽  
Vol 17 (8) ◽  
pp. 501-506 ◽  
Author(s):  
Marc Bilodeau
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Diseases ◽  
Hepatocyte Apoptosis ◽  
Main Mode ◽  
The Past ◽  
Extracellular Environment ◽  
Cardinal Feature ◽  
Liver Cell Death ◽  
Biochemical Features

Hepatocyte cell death is a cardinal feature of almost every liver disease. Apoptosis is a mode of cell death characterized by specific morphological and biochemical features. Over the past decade, the importance of apoptosis has been appreciated, and it is now thought to be the main mode of cell death in liver diseases. The recognition that apoptosis can be modulated by the cell itself or by the extracellular environment has given hope that treatments can be designed to modify the evolution of disease. This article presents an overview of this important phenomenon, as well as models of hepatocyte apoptosis and goals of current research. The significance of apoptosis to the pathophysiology of liver disease is discussed.

scholarly journals Mitochondrial Mechanisms of Apoptosis and Necroptosis in Liver Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qingfei Chu ◽  
Xinyu Gu ◽  
Qiuxian Zheng ◽  
Jing Wang ◽  
Haihong Zhu
Keyword(s):  
Cell Death ◽  
Liver Cirrhosis ◽  
Liver Disease ◽  
Programmed Cell Death ◽  
Liver Diseases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Cellular Energetics ◽  
Liver Cell Death

In addition to playing a pivotal role in cellular energetics and biosynthesis, mitochondrial components are key operators in the regulation of cell death. In addition to apoptosis, necrosis is a highly relevant form of programmed liver cell death. Differential activation of specific forms of programmed cell death may not only affect the outcome of liver disease but may also provide new opportunities for therapeutic intervention. This review describes the role of mitochondria in cell death and the mechanism that leads to chronic liver hepatitis and liver cirrhosis. We focus on mitochondrial-driven apoptosis and current knowledge of necroptosis and discuss therapeutic strategies for targeting mitochondrial-mediated cell death in liver diseases.

scholarly journals Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

2021 ◽  
Vol 22 (15) ◽  
pp. 8253
Author(s):  
Jung-Yeon Kim ◽  
Yongmin Choi ◽  
Jaechan Leem ◽  
Jeong Eun Song
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Heme Oxygenase ◽  
Murine Model ◽  
Liver Diseases ◽  
Transforming Growth Factor ◽  
Heme Oxygenase 1 ◽  
Cholestatic Liver Disease ◽  
Hepatocyte Apoptosis ◽  
Cobalt Protoporphyrin

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

scholarly journals Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients

2019 ◽  
Vol 316 (1) ◽  
pp. G115-G122 ◽  
Author(s):  
Vatsalya Vatsalya ◽  
Maiying Kong ◽  
Leila Gobejishvili ◽  
Wei-Yang Chen ◽  
Sanjay Srivastava ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Proinflammatory Cytokines ◽  
Alcoholic Hepatitis ◽  
Pathogenic Role ◽  
Cytokeratin 18 ◽  
Acute Alcoholic Hepatitis ◽  
Noninvasive Biomarker ◽  
Liver Cell Death

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe [model for end-stage liver disease (MELD) ≥ 20] AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R2 = 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R2 = 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 = 0.875, P = 0.007) and CK18-M65 (adjusted R2 = 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 = 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R2 = 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.

scholarly journals Ferroptosis in liver disease: new insights into disease mechanisms

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jing Wu ◽  
Yi Wang ◽  
Rongtao Jiang ◽  
Ran Xue ◽  
Xuehong Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Diseases ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Iron Accumulation ◽  
Related Factor ◽  
Drug Induced ◽  
Nonalcoholic Fatty Liver

AbstractCharacterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other well-known cell death. In recent years, ferroptosis has been quickly gaining attention in the field of liver diseases, as the liver is predisposed to oxidative injury and generally, excessive iron accumulation is a primary characteristic of most major liver diseases. In the current review, we first delineate three cellular defense mechanisms against ferroptosis (GPx4 in the mitochondria and cytosol, FSP1 on plasma membrane, and DHODH in mitochondria), along with four canonical modulators of ferroptosis (system Xc−, nuclear factor erythroid 2-related factor 2, p53, and GTP cyclohydrolase-1). Next, we review recent progress of ferroptosis studies delineating molecular mechanisms underlying the pathophysiology of several common liver diseases including ischemia/reperfusion-related injury (IRI), nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hemochromatosis (HH), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Furthermore, we also highlight both challenges and promises that emerged from recent studies that should be addressed and pursued in future investigations before ferroptosis regulation could be adopted as an effective therapeutic target in clinical practice.

scholarly journals New Therapies of Liver Diseases: Hepatic Encephalopathy

2021 ◽  
Vol 10 (18) ◽  
pp. 4050
Author(s):  
Chiara Mangini ◽  
Sara Montagnese
Keyword(s):  
Liver Disease ◽  
Hepatic Encephalopathy ◽  
Liver Diseases ◽  
Management Strategies ◽  
New Drugs ◽  
Common Complication ◽  
Advanced Liver Disease ◽  
The Past ◽  
Significant Burden ◽  
Management Challenge

Hepatic encephalopathy (HE) is a common complication of advanced liver disease which has profound implications in terms of the patients’ ability to fulfil their family and social roles, to drive and to provide for themselves. Recurrent and persistent HE is still a serious management challenge, translating into a significant burden for patients and their families, health services and society at large. The past few years have been characterized by significantly more attention towards HE and its implications; its definition has been refined and a small number of new drugs/alternative management strategies have become available, while others are underway. In this narrative review we summarize them in a pragmatic and hopefully useful fashion.

Epidemiology of chronic liver diseases in the USA in the past three decades

Gut ◽  
2019 ◽  
Vol 69 (3) ◽  
pp. 564-568 ◽  
Author(s):  
Zobair M Younossi ◽  
Maria Stepanova ◽  
Youssef Younossi ◽  
Pegah Golabi ◽  
Alita Mishra ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Liver Disease ◽  
Fatty Liver ◽  
Liver Diseases ◽  
Cross Sectional ◽  
Alcoholic Fatty Liver ◽  
The Past ◽  
Fatty Liver Index ◽  
Health And Nutrition ◽  
The Usa

ObjectiveGiven significant advances in treatment of viral hepatitis and the growing epidemic of obesity, the burden of the different types of liver diseases in the USA may be changing. Our aim was to assess the shift in the prevalence of different liver disease aetiologies in the USA over the past three decades.DesignNational Health and Nutrition Examination Surveys (NHANES; cross-sectional 1988–1994 and 1999–2016) were used.ResultsA total of 58 731 adults from NHANES (1988–2016) were included. Over the study period, the prevalence of chronic hepatitis B and alcoholic liver disease remained stable: 0.3%–0.4% and 0.8%–1.0%, respectively (p>0.05). The prevalence of chronic hepatitis C decreased nearly twofold: 1.6% in 1988–1994 to 0.9% in 2013–2016 (p=0.03). In contrast, the prevalence of non-alcoholic fatty liver disease (NAFLD; by US-Fatty Liver Index) increased from 20.0% (1988–1994) to 28.3% (1999–2004) to 33.2% (2009–2012) and 31.9% (2013–2016) (p<0.0001). Furthermore, steady increases were observed in the rates of obesity (22.2% in 1988–1994 to 31.0% in 1999–2004 to 38.9% in 2013–2016), type 2 diabetes mellitus (T2DM) (from 7.2% to 8.2% to 13.5% same years), insulin resistance and hypertension (all p<0.0001). Yearly trend analyses showed that the only LD with consistently increasing prevalence was NAFLD (trend p=0.01). Multivariable regression analysis showed that obesity (OR 10.4; 95% CI 9.5 to 11.3) and T2DM (OR 3.7; 95% CI 3.2 to 4.2) were the major independent predictors of NAFLD.ConclusionsOver the past 30 years in the USA, NAFLD is the only liver disease with growing prevalence, synchronous with the increasing rates of obesity and T2DM.

scholarly journals Identification of Serum Biomarkers in End Stage Liver Disease

2010 ◽  
Vol 3 (1) ◽  
pp. 1-6
Author(s):  
D. Koutsogiannis ◽  
K. Summers ◽  
B. George ◽  
P. Adams ◽  
P. Marotta ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Diseases ◽  
Serum Markers ◽  
Control Group ◽  
Serum Samples ◽  
Alcoholic Fatty Liver ◽  
End Stage Liver Disease ◽  
Luminex Technology ◽  
End Stage

Background: Progressive fibrosis and cirrhosis, clinically presenting as end-stage liver disease are common outcomes in alcoholic hepatitis as well as non-alcoholic fatty liver disease(NAFLD). In these processes, a series of changes occurs in liver tissues leading to cell death, remodeling, fibrosis and regeneration. The aim of this study is to identify potential novel biomarkers for non-invasive diagnosis of cirrhosis due to alcoholic etiology or NAFLD. Methods: Serum from patients with biopsy proven end-stage liver disease of various etiologies, namely NAFLD(n=9), alcohol( n=5), and other end-stage liver diseases(n=6), who underwent liver transplant during the first six months of 2007 were utilized for retrospective analysis. Serum samples were also collected from a group of healthy volunteers (n=7). The samples were analysed using Luminex technology or ELISA for 27 biomarkers that are known to be involved in pathologic processes such as cell death, regeneration and fibrosis. Results: Of the 27 serum markers examined, 16 were elevated in the serum in all groups with end-stage liver diseases compared with the control group. They include adipokines, apoptosis and inflammatory mediators and growth factors. Interestingly, the serum of NAFLD patients showed significantly elevated HGF levels and trend towards increase in sFAS, TGF􀀁1, TNFR-1, TNFR-2 and leptin. The level of serum markers showed excellent correlation with each other indicating a complex interdependent pathogenetic mechanism. Conclusions: The data from this study indicate that a large number of serum markers are altered in end-stage liver diseases. A panel of such markers may potentially be useful in assessing advanced fibrosis and cirrhosis in patients with chronic end stage liver diseases.

scholarly journals Cell Death in Liver Diseases: A Review

2020 ◽  
Vol 21 (24) ◽  
pp. 9682
Author(s):  
Layla Shojaie ◽  
Andrea Iorga ◽  
Lily Dara
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Injury ◽  
Liver Diseases ◽  
Disease Model ◽  
Current Data ◽  
Critical Event ◽  
Cholestatic Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Cell Death Pathway

Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.

scholarly journals Evaluation of circulating cell-free DNA in cholestatic liver disease using liver-specific methylation markers

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sohan Punia ◽  
Brian D. Juran ◽  
Ahmad H. Ali ◽  
Erik M. Schlicht ◽  
Raymond M. Moore ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Diseases ◽  
Methylation Status ◽  
Primary Biliary Cholangitis ◽  
Specific Cell ◽  
Cholestatic Liver Disease ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna

Abstract Background Quantification of circulating organ-specific cell-free DNA (cfDNA) provides a sensitive measure of ongoing cell death that could benefit evaluation of the cholestatic liver diseases primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which lack reliable non-invasive biomarkers. Our goal in this pilot study was to determine whether liver-specific cfDNA levels are increased in PBC and PSC patients relative to controls and in advanced versus early disease, to evaluate their potential as novel disease biomarkers. Methods Peripheral blood derived bisulfite-treated DNA was PCR amplified from patients with PBC (n = 48), PSC (n = 48) and controls (n = 96) to evaluate methylation status at 16 CpG sites reported to be specifically unmethylated in liver tissue near the genes IGF2R, ITIH4 and VTN. Amplicons were used to prepare paired end libraries which were sequenced on a MiSeq sequencer. Trimmed reads were aligned and used to determine unmethylation ratios and to calculate concentration of liver-specific cfDNA. Comparisons between groups were performed using the two-tailed Mann–Whitney Test and relationships between variables were evaluated using Pearson’s Correlation. Results Levels of liver-specific cfDNA, as measured at the 3 genetic loci, were increased in PBC and PSC patients relative to controls and in late-stage relative to early-stage patients. As well, cfDNA levels were correlated with levels of alkaline phosphatase, a commonly used biochemical test to evaluate disease severity in liver disease, in patients, but not in controls. Conclusions cfDNA offers promise as a non-invasive liquid-biopsy to evaluate liver-specific cell-death in patients with cholestatic liver diseases.

Genetics in Common Liver Diseases: From Pathophysiology to Precise Treatment

2016 ◽  
Vol 34 (4) ◽  
pp. 391-395 ◽  
Author(s):  
Frank Lammert
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Association Studies ◽  
Clinical Care ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
The Past ◽  
Genomic Technologies ◽  
Genome Wide

In the past 2 decades, advances in genetics have improved our understanding of liver disease and physiology. Firstly, developments in genomic technologies drove the identification of genes responsible for monogenic (Mendelian) liver diseases. Over the last decade, genome-wide association studies allowed for the dissection of the genetic susceptibility to complex liver diseases such as fatty liver disease and drug-induced liver injury, in which environmental co-factors play critical roles. The findings have allowed the identification and elaboration of pathophysiological processes, have indicated the need for reclassification of liver diseases and risk factors and have already pointed to new disease treatments. This is illustrated by the interaction of alcohol, overnutrition and the PNPLA3 gene, which represents an ‘infernal triangle' for the liver. In the future, genetics will allow further stratification of liver diseases and contribute to personalized (precision) medicine, offering novel opportunities for translational research and clinical care of our patients.

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