Abstract:Apoptotic hepatocytes release factors that activate hepatic stellate cells (HSCs), thereby inducing hepatic fibrosis. In the present study, in vivo and in vitro injury models were established using acetaminophen, ethanol, carbon tetrachloride, or thioacetamide. Histology of hepatotoxicant-induced diseased hepatic tissue correlated with differential expression of fibrosis-related genes. A marked increase in co-staining of transforming growth factor β receptor type II (TGFRIIβ) - desmin or α-smooth muscle actin … Show more
“…Moreover, the most robust functional profiles among these signatures included genes coding for ECM proteins and membrane receptors (Fig. 6 and Table S2 ), which were largely represented in HSCs ( CXCL6 , COL4A2 , COL4A1 , LAMC3 , BTG2 , THBS2 ) and which are also members of the overrepresented PDGF signaling pathway (see Table S2 ) which is known to activate epithelial-mesenchymal transition (EMT) in HSCs and promote fibrogenic signals 44 .…”
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.
“…Moreover, the most robust functional profiles among these signatures included genes coding for ECM proteins and membrane receptors (Fig. 6 and Table S2 ), which were largely represented in HSCs ( CXCL6 , COL4A2 , COL4A1 , LAMC3 , BTG2 , THBS2 ) and which are also members of the overrepresented PDGF signaling pathway (see Table S2 ) which is known to activate epithelial-mesenchymal transition (EMT) in HSCs and promote fibrogenic signals 44 .…”
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. In adults with NAFLD, fibrosis can develop and progress to liver cirrhosis and liver failure. However, the underlying molecular mechanisms of fibrosis progression are not fully understood. Using total RNA-Seq, we investigated the molecular mechanisms of NAFLD and fibrosis. We sequenced liver tissue from 143 adults across the full spectrum of fibrosis stage including those with stage 4 fibrosis (cirrhosis). We identified gene expression clusters that strongly correlate with fibrosis stage including four genes that have been found consistently across previously published transcriptomic studies on NASH i.e. COL1A2, EFEMP2, FBLN5 and THBS2. Using cell type deconvolution, we estimated the loss of hepatocytes versus gain of hepatic stellate cells, macrophages and cholangiocytes with advancing fibrosis stage. Hepatocyte-specific functional analysis indicated increase of pro-apoptotic pathways and markers of bipotent hepatocyte/cholangiocyte precursors. Regression modelling was used to derive predictors of fibrosis stage. This study elucidated molecular and cell composition changes associated with increasing fibrosis stage in NAFLD and defined informative gene signatures for the disease.
“…79 During injury, hepatocytes and Kupffer cells can be important source of TGF-β. 80,81 TGF-β is a key inducer of fibrosis, activating HSCs into aHSCs and transdifferentiating hepatocytes toward myofibroblasts through an EMT-like process. 82 TGF-β increased matrix deposition of HSCs through inducing connective tissue growth factor (CTGF), receptor for activated c kinase 1 and NADPH oxidase 4 signaling, and collagen-1 secretion.…”
Section: Tgf-β Signaling In Healthy and Diseased Livermentioning
The presence of liver metastases drastically worsens the prognosis of cancer patients. The liver is the second most prevalent metastatic site in cancer patients, but systemic therapeutic opportunities that target liver metastases are still limited. To aid the discovery of novel treatment options for metastatic liver disease, we provide insight into the cellular and molecular steps required for liver colonization. For successful colonization in the liver, adaptation of tumor cells and surrounding stroma is essential. This includes the formation of a pre-metastatic niche, the creation of a fibrotic and immune suppressive environment, angiogenesis, and adaptation of tumor cells. We illustrate that transforming growth factor β (TGF-β) is a central cytokine in all these processes. At last, we devise that future research should focus on TGF-β inhibitory strategies, especially in combination with immunotherapy. This promising systemic treatment strategy has potential to eliminate distant metastases as the efficacy of immunotherapy will be enhanced.
“…Lipopolysaccharide (LPS), a component of the cell walls of some gram-negative bacteria that normally inhabit the intestine, is one substance that can effectively activate Kupffer cells 97,98 . The activated Kupffer cells produce several cytokines and growth factors such as tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), platelet derived growth factor (PDGF), and interleukin (IL)−1β which in turn activate and transform the quiescent HSCs into myofibroblast like cells 99–101 .Fig. 3Schematic representation of the cellular interactions and molecular mechanisms involved in the pathogenesis of N -nitrosodimethylamine induced hepatic fibrosis.Hepatocyte injury leads to inflammation and generation of reactive oxygen species that in turn activate Kupffer cells.…”
Section: Cellular Interactions and Molecular Mechanisms In The Pathogmentioning
Hepatic fibrosis is marked by excessive synthesis and deposition of connective tissue proteins, especially interstitial collagens in the extracellular matrix of the liver. It is a result of an abnormal wound healing in response to chronic liver injury from various causes such as ethanol, viruses, toxins, drugs, or cholestasis. The chronic stimuli involved in the initiation of fibrosis leads to oxidative stress and generation of reactive oxygen species that serve as mediators of molecular events involved in the pathogenesis of hepatic fibrosis. These processes lead to cellular injury and initiate inflammatory responses releasing a variety of cytokines and growth factors that trigger activation and transformation of resting hepatic stellate cells into myofibroblast like cells, which in turn start excessive synthesis of connective tissue proteins, especially collagens. Uncontrolled and extensive fibrosis results in distortion of lobular architecture of the liver leading to nodular formation and cirrhosis. The perpetual injury and regeneration process could also results in genomic aberrations and mutations that lead to the development of hepatocellular carcinoma. This review covers most aspects of the molecular mechanisms involved in the pathogenesis of hepatic fibrosis with special emphasize on
N
-Nitrosodimethylamine (NDMA; Dimethylnitorsmaine, DMN) as the inducing agent.
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