Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C

Tanwar, Sudeep; Rhodes, Freya; Srivastava, Ankur; Trembling, Paul M.; Rosenberg, William

doi:10.3748/wjg.v26.i2.109

Cited by 151 publications

(99 citation statements)

References 164 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, we investigate specific outcomes of DNA methylation loss in zebrafish livers. We focus on the liver because inflammation plays a central role in several important liver diseases, including viral and non-viral hepatitis, which, in the setting of fatty liver can progress to a life threatening steatohepatitis (21) and the inflammation during hepatic fibrosis can severely reduce liver function and regenerative capacity (22). Some studies have uncovered inappropriate TE activation as a common feature of liver cancer (23,24) and in other cancer types, viral mimicry by TEs has been proposed to trigger activation of the interferon response (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

et al. 2021

View full text Add to dashboard Cite

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

show abstract

Section: Introductionmentioning

confidence: 99%

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Insulin resistance is an inflammatory condition [ 38 , 39 , 40 ], and disruption of the liver’s metabolic system activates immune and inflammatory pathways that can further exacerbate metabolic perturbations that feed forward to NAFLD ( Figure 4 ). These perturbations include tissue damage, steatohepatitis, and fibrosis [ 41 , 42 ]. Hepatocyte; hepatic stellate cell; sinusoidal endothelial cell; and Kupffer cell stress responses to lipotoxicity, metabolic dysregulation, and oxidative stress can all increase inflammatory cytokine release, innate intracellular immune reactivity, and immune cell recruitment and activation [ 43 , 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Rostama

Beauchemin

Bouchard

et al. 2020

IJMS

View full text Add to dashboard Cite

Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.

show abstract

“…Liver fibrosis is a complex process involving multiple inflammatory signaling cascades [ 48 ]. HSCs are considered the most relevant sources of hepatic myofibroblasts involved in liver fibrogenesis [ 49 ], and oxidative stress is critical in HSC stimulation through activation of NF-κB during this process [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Finamor

Bressan

Torres-Cuevas

et al. 2021

Biology

View full text Add to dashboard Cite

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

show abstract

Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C

Cited by 151 publications

References 164 publications

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Contact Info

Product

Resources

About