scholarly journals New Developments on the Treatment of Liver Fibrosis

2016 ◽  
Vol 34 (5) ◽  
pp. 589-596 ◽  
Author(s):  
Yukinori Koyama ◽  
Jun Xu ◽  
Xiao Liu ◽  
David A. Brenner
Keyword(s):  
Liver Fibrosis ◽  
Current Knowledge ◽  
Stellate Cells ◽  
Matrix Proteins ◽  
New Developments ◽  
Liver Myofibroblasts ◽  
Advanced Stages ◽  
Chronic Injuries ◽  
Hepatocyte Damage ◽  
New Strategies

Liver fibrosis results from many chronic injuries and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation, which leads to the activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins, which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis.

scholarly journals Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 24 ◽  
Author(s):  
Olga Khomich ◽  
Alexander V. Ivanov ◽  
Birke Bartosch
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Current Knowledge ◽  
Stellate Cells ◽  
Central Carbon Metabolism ◽  
Regenerative Process ◽  
Therapeutic Interventions ◽  
Alcoholic Fatty Liver ◽  
Liver Functions

Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.

Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis

2000 ◽  
Vol 279 (2) ◽  
pp. G245-G249 ◽  
Author(s):  
Michael J. P. Arthur
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Matrix Proteins ◽  
Gelatinase A ◽  
Fibrotic Liver ◽  
Fibrillar Collagens ◽  
Membrane Type ◽  
Interstitial Collagenase

Liver fibrosis is characterized by activation of hepatic stellate cells, which are then involved in synthesis of matrix proteins and in regulating matrix degradation. In the acute phases of liver injury and as liver fibrosis progresses, there is increased expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Among the changes described, striking features include increased expression of gelatinase A (MMP-2) and membrane type 1-MMP (MT1-MMP; MMP-14) as well as TIMP-1 and TIMP-2. These molecules and other family members are involved in regulating degradation of both normal and fibrotic liver matrix. This article outlines recent progress in this field and discusses the mechanisms by which MMPs and TIMPs may contribute to the progression and regression of liver fibrosis. Recently described properties of MMPs and TIMPs of relevance to the pathogenesis of liver fibrosis are outlined. The proposal that regression of liver fibrosis is mediated by decreased expression of TIMPs and involves degradation of fibrillar collagens by a combination of MT1-MMP and gelatinase A, in addition to interstitial collagenase, is explored.

scholarly journals IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH

2018 ◽  
Author(s):  
Anissa A. Widjaja ◽  
Brijesh K. Singh ◽  
Eleonora Adami ◽  
Sivakumar Viswanathan ◽  
Giuseppe A. D’Agostino ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Cells ◽  
Hepatic Stellate Cells ◽  
Neutralizing Antibodies ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Activation Loop ◽  
Liver Inflammation ◽  
Preclinical Models ◽  
Hepatocyte Damage

AbstractThe transformation of hepatic stellate cells (HSCs) into myofibroblasts is the defining pathobiology in non-alcoholic steatohepatitis (NASH). Here we show that key NASH factors induce IL-11, which drives an autocrine and ERK-dependent activation loop to initiate and maintain HSC-to-myofibroblast transformation, causing liver fibrosis. IL-11 is upregulated in NASH andIl11ra1-deleted mice are strongly protected from liver fibrosis, inflammation and steatosis in murine NASH. Therapeutic inhibition of IL11RA or IL-11 with novel neutralizing antibodies robustly inhibits NASH pathology in preclinical models and reverses established liver fibrosis by promoting HSC senescence and favourable matrix remodelling. When given early in NASH, IL-11 inhibition prevents liver inflammation and steatosis, reverses severe hepatocyte damage and reduces hepatic immune cells and TGFβ1 levels. Our findings show an unappreciated and central role for IL-11 in HSCs and prioritise IL-11 signalling as a new therapeutic target in NASH while revealing an unexpected pro-inflammatory function for IL-11 in stromal immunity.

scholarly journals Activated hepatic stellate cells upregulate transcription of ecto-5′-nucleotidase/CD73 via specific SP1 and SMAD promoter elements

2012 ◽  
Vol 303 (8) ◽  
pp. G904-G914 ◽  
Author(s):  
Michel Fausther ◽  
Nina Sheung ◽  
Yedidya Saiman ◽  
Meena B. Bansal ◽  
Jonathan A. Dranoff
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Regulatory Elements ◽  
Site Directed Mutagenesis ◽  
Transcriptional Level ◽  
Promoter Elements ◽  
Fibrotic Liver ◽  
Liver Myofibroblasts ◽  
Cellular Marker

Adenosine is a potent modulator of liver fibrosis and inflammation. Adenosine has been shown to regulate such diverse activities as chemotaxis, contraction, and matrix production in hepatic stellate cells (HSC). Ecto-5′-nucleotidase/CD73 [EC 3.1.3.5] is the rate-limiting enzyme in adenosine production. Cd73-deficient mice are resistant to experimental liver fibrosis and have impaired adenosine generation. However, cell-specific expression and regulation of CD73 within the fibrotic liver have not been defined. In particular, prior evidence demonstrating that liver myofibroblasts, the cells believed to be responsible for matrix formation in the liver, express CD73 is lacking. Thus we tested the hypothesis that HSC and portal fibroblasts (PF), cells that undergo differentiation into liver myofibroblasts, express CD73 in a regulated fashion. We found that CD73 is weakly expressed in quiescent HSC and PF but is markedly upregulated at the transcriptional level in myofibroblastic HSC and PF. We furthermore found that CD73 protein and its functional activity are strongly increased in fibrous septa in rats subjected to experimental fibrosis. To determine the mechanism for the upregulation of Cd73 gene, we cloned the rat Cd73 promoter and then used serial truncation and site-directed mutagenesis to identify key regulatory elements. We identified two consensus SP1 motifs and one SMAD binding site, each of which was necessary for Cd73 gene upregulation. In conclusion, activated HSC upregulate Cd73 gene expression, via specific SP1 and SMAD promoter elements, after myofibroblastic differentiation. The ecto-5′-nucleotidase/CD73 enzyme is a novel cellular marker of activated liver myofibroblasts in vivo and in vitro and thus represents a promising molecular target for antifibrotic therapies in liver diseases.

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