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Cells Apr 2020Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key... (Review)
Review
Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
Topics: Animals; Apoptosis; Gastrointestinal Microbiome; Humans; Liver Cirrhosis; Models, Biological; Oxidative Stress; Signal Transduction
PubMed: 32260126
DOI: 10.3390/cells9040875 -
Molecular Aspects of Medicine Feb 2019The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as... (Review)
Review
The progression of chronic liver diseases (CLD), irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response as well as sustained activation of liver fibrogenesis and wound healing response. Liver fibrogenesis, is a dynamic, highly integrated molecular, cellular and tissue process responsible for driving the excess accumulation of extracellular matrix (ECM) components (i.e., liver fibrosis) sustained by an eterogeneous population of hepatic myofibroblasts (MFs). The process of liver fibrogenesis recognizes a number of common and etiology-independent mechanisms and events but it is also significantly influenced by the specific etiology, as also reflected by peculiar morphological patterns of liver fibrosis development. In this review we will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets, to finally analyze selected and relevant clinical issues.
Topics: Animals; Biomarkers; Cellular Microenvironment; Chronic Disease; Disease Progression; Disease Susceptibility; Energy Metabolism; Extracellular Matrix; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Liver Diseases; Myofibroblasts; Signal Transduction
PubMed: 30213667
DOI: 10.1016/j.mam.2018.09.002 -
Nature Reviews. Gastroenterology &... Mar 2021Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate... (Review)
Review
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
Topics: Hepatic Stellate Cells; Hepatocytes; Humans; Liver Cirrhosis; Myofibroblasts
PubMed: 33128017
DOI: 10.1038/s41575-020-00372-7 -
The Journal of Clinical Investigation Feb 2005Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver... (Review)
Review
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
Topics: Angiotensin II; Animals; Humans; Hypertension, Portal; Leptin; Liver Cirrhosis; Liver Failure; Transforming Growth Factor beta
PubMed: 15690074
DOI: 10.1172/JCI24282 -
The Turkish Journal of Gastroenterology... Jan 2018Liver fibrosis is a wound-healing response generated against an insult to the liver that causes liver injury. It has the potential to progress into cirrhosis, and if not... (Review)
Review
Liver fibrosis is a wound-healing response generated against an insult to the liver that causes liver injury. It has the potential to progress into cirrhosis, and if not prevented, it may lead to liver cancer and liver failure. The activation of hepatic stellate cells (HSCs) is the central event underlying liver fibrosis. In addition to HSCs, numerous studies have supported the potential contribution of bone marrow-derived cells and myofibroblasts to liver fibrosis. The liver is a heterogeneous organ; thus, molecular and cellular events that underlie liver fibrogenesis are complex. This review aims to focus on major events that occur during liver fibrogenesis. In addition, important antifibrotic therapeutic approaches and experimental liver fibrosis models will be discussed.
Topics: Fibrosis; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Liver Neoplasms; Macrophages; Myofibroblasts
PubMed: 29391303
DOI: 10.5152/tjg.2018.17330 -
Annual Review of Pathology 2011Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver disease associated with obesity.... (Review)
Review
Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver disease associated with obesity. Hepatic stellate cell activation represents a critical event in fibrosis because these cells become the primary source of extracellular matrix in liver upon injury. Use of cell-culture and animal models has expanded our understanding of the mechanisms underlying stellate cell activation and has shed new light on genetic regulation, the contribution of immune signaling, and the potential reversibility of the disease. As pathways of fibrogenesis are increasingly clarified, the key challenge will be translating new advances into the development of antifibrotic therapies for patients with chronic liver disease.
Topics: Humans; Liver; Liver Cirrhosis; Signal Transduction
PubMed: 21073339
DOI: 10.1146/annurev-pathol-011110-130246 -
Cells Oct 2021Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix.... (Review)
Review
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
Topics: Animals; Extracellular Matrix; Humans; Inflammation; Liver Cirrhosis; Myofibroblasts; Remission Induction; Vascular Remodeling
PubMed: 34685739
DOI: 10.3390/cells10102759 -
Gastroenterology Clinics of North... Jun 2019All chronic liver disease can lead to liver fibrosis. Assessment of the severity of liver fibrosis is central to making treatment and management decisions. Liver biopsy,... (Review)
Review
All chronic liver disease can lead to liver fibrosis. Assessment of the severity of liver fibrosis is central to making treatment and management decisions. Liver biopsy, the gold standard for liver fibrosis assessment, is invasive and carries risks of complications and sampling errors. The use of noninvasive elastography-based radiologic methods of liver fibrosis determination is limited to centers that have the capabilities. Laboratory liver fibrosis determinations, both general clinical scoring systems and combination biomarker panels, are accessible to a wider population of clinicians for identifying patients at low risk of advanced fibrosis who do not need liver biopsies.
Topics: Biomarkers; Biopsy; Chronic Disease; Clinical Laboratory Techniques; Female; Humans; Liver Cirrhosis; Liver Diseases; Male; Radiography; Risk
PubMed: 31046975
DOI: 10.1016/j.gtc.2019.02.002 -
Journal of Advanced Research May 2023High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.
INTRODUCTION
High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.
OBJECTIVES
This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation.
METHODS
The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression.
RESULTS
ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo.
CONCLUSIONS
Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Liver Cirrhosis; Inflammation; Signal Transduction; Angiopoietin-Like Protein 8
PubMed: 36031141
DOI: 10.1016/j.jare.2022.08.006 -
World Journal of Gastroenterology Jun 2015Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.
Topics: Biomarkers; Biopsy; Disease Progression; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Prognosis; Severity of Illness Index
PubMed: 26139988
DOI: 10.3748/wjg.v21.i24.7427