Collagen Characterization in a Model of Nonalcoholic Steatohepatitis with Fibrosis; A Call for Development of Targeted Therapeutics

Pellicano, A; Spahn, Kiera; Zhou, Ping; Goldberg, Itzhak D.; Narayan, Prakash

doi:10.3390/molecules26113316

Cited by 16 publications

(18 citation statements)

References 24 publications

(64 reference statements)

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“…Collagen is the principal component of the extracellular matrix or scars. A recent study showed that NASH with fibrosis is associated with upregulation of hepatic fibrillar collagen genes, namely, COL I and COL III [61]. Most studies on animals fed an HFD diet for a duration of less than 4 months showed that there were no significant changes in the expression of genes encoding proteins involved in the fibrogenesis pathway; however, such changes were found to be significant in studies with a longer duration from 24-25 weeks of exposure to HFD [22,45] (Table 5).…”

Section: Fibrogenesis Pathwaymentioning

confidence: 99%

A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) embraces several forms of liver disorders involving fat disposition in hepatocytes ranging from simple steatosis to the severe stage, namely, non-alcoholic steatohepatitis (NASH). Recently, several experimental in vivo animal models for NAFLD/NASH have been established. However, no reproducible experimental animal model displays the full spectrum of pathophysiological, histological, molecular, and clinical features associated with human NAFLD/NASH progression. Although methionine-choline-deficient (MCD) diet and high-fat diet (HFD) models can mimic histological and metabolic abnormalities of human disease, respectively, the molecular signaling pathways are extremely important for understanding the pathogenesis of the disease. This review aimed to assess the differences in gene expression patterns and NAFLD/NASH progression pathways among the most common dietary animal models, i.e., HFD- and MCD diet-fed animals. Studies showed that the HFD and MCD diet could induce either up- or downregulation of the expression of genes and proteins that are involved in lipid metabolism, inflammation, oxidative stress, and fibrogenesis pathways. Interestingly, the MCD diet model could spontaneously develop liver fibrosis within two to four weeks and has significant effects on the expression of genes that encode proteins and enzymes involved in the liver fibrogenesis pathway. However, such effects in the HFD model were found to occur after 24 weeks with insulin resistance but appear to cause less severe fibrosis. In conclusion, assessing the abnormal gene expression patterns caused by different diet types provides valuable information regarding the molecular mechanisms of NAFLD/NASH and predicts the clinical progression of the disease. However, expression profiling studies concerning genetic variants involved in the development and progression of NAFLD/NASH should be conducted.

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Section: Fibrogenesis Pathwaymentioning

confidence: 99%

A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet

et al. 2022

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“…We explored lncRNA responses in chronic CCl 4 -exposed liver, a widely used model for chemical-induced liver fibrosis and identified 631 lncRNAs dysregulated in or more hepatic mesenchymal cell populations. Validating this model, we observed strong up regulation of many HSC-expressed lncRNAs in association with the up regulation of PCGs involved in extracellular matrix and collagen processes, a key feature of HSC activation and liver fibrosis 128 . Further, spatial inference analysis revealed apparent zonation differences between control and fibrotic HSCs.…”

Section: Discussionmentioning

confidence: 72%

Dysregulation of murine long non-coding single cell transcriptome in non-alcoholic steatohepatitis and liver fibrosis

Karri

Waxman

2022

Preprint

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LncRNAs are typified by low expression, nuclear enrichment, high tissue-specificity and functional diversity, but the vast majority are uncharacterized. Here, we develop a catalog of 48,000 mouse liver-expressed lncRNAs and use to elucidate lncRNA dysregulation in high fat diet-induced non-alcoholic steatohepatitis and carbon tetrachloride-induced liver fibrosis by single cell RNA-seq. LncRNA zonation patterns across the liver lobule were discovered in five cell populations. Perturbations in lncRNA expression were common in disease-associated cell types, including non-alcoholic steatohepatitis-associated macrophages, a hallmark of fatty liver disease progression, and collagen-producing myofibroblasts, key to liver fibrosis. Gene regulatory network analysis linked individual lncRNAs to biological pathways and network centrality metrics identified network-essential, disease-associated regulatory lncRNAs. Regulatory lncRNAs with network-predicted target gene promoters enriched for triplex-based lncRNA binding were also identified. These findings elucidate hepatic lncRNA cell-type specificities, spatial zonation patterns, linked biological networks and dysregulation in disease progression. A subset of the disease-associated lncRNAs have human orthologs and are promising candidates for biomarkers and therapeutic targets.

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“…The major fibrillar collagens abundantly expressed in liver fibrosis are Collagen 1 and Collagen 3 ( Pellicano et al, 2021 ). We have investigated both ICV and IP CBX groups to evaluate our previous findings further and investigate possible treatment targets by mitigating excessive fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…We have checked the Collagen 1 and Collagen 3 expression in spinal cord sections and pointed accumulation of Collagen 3 in the PLP group, and prevention of perivascular fibrosis by CBX treatment. One possible explanation for this could be that extensive Collagen 1 accumulation is the hallmark of advanced fibrosis in the liver; whereas, fibrillar Collagen 3 expression starts in the early stages and gradually increases regarding the severity of the disease ( Pellicano et al, 2021 ). We showed that IP CBX did not alter the collagen 3 production but ICV CBX significantly decreased the Collagen 3 accumulation in-vivo .…”

Section: Discussionmentioning

confidence: 99%

Carbenoxolone mitigates extensive fibrosis formation in PLP-induced EAE model and multiple sclerosis serum-exposed pericyte culture

Ucar,

Ozkan,

Shomalizadeh

et al. 2024

Front. Cell. Neurosci.

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IntroductionMultiple sclerosis (MS) is one of the most common causes of disability in young adults. Nearly, 85% of MS cases start with attacks and remissions, classified as relapsing-remitting multiple sclerosis (RRMS). With repeating attacks, MS causes brain-spinal cord atrophy and enhanced disability as disease progresses. PLP-induced EAE is one of the most established models for pathophysiology and treatment of RRMS. Recent studies demonstrated the possible role of pericytes in perivascular and intra-lesional fibrosis in PLP-induced EAE, whose importance remains elusive. Hence, we have investigated the possible role of pericytes in fibrosis formation and amelioration with a hemichannel blocker, Carbenoxolone (CBX).MethodsPLP-induced experimental autoimmune encephalitis (EAE) model is used and the effect of CBX is investigated. Clinical scores were recorded and followed. Perivascular Collagen 1 and 3 accumulations were demonstrated as markers of fibrosis in the spinal cord. To delineate the role of pericytes, human brain vascular pericytes (HBVP) were incubated with the sera of MS patients to induce in-vitro MS model and the fibrosis formation was investigated.ResultsIn the PLP induced in-vivo model, both intracerebroventricular and intraperitoneal CBX have significantly mitigated the disease progression followed by clinical scores, demyelination, and fibrosis. Moreover, CBX significantly mitigated MS-serum-induced fibrosis in the HBVP cell culture.DiscussionThe study demonstrated two important findings. First, CBX decreases fibrosis formation in both in-vivo and in-vitro MS models. Secondly, it improves neurological scores and decreases demyelination in the EAE model. Therefore, CBX can be potential novel therapeutic option in treating Multiple Sclerosis.

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Collagen Characterization in a Model of Nonalcoholic Steatohepatitis with Fibrosis; A Call for Development of Targeted Therapeutics

Cited by 16 publications

References 24 publications

A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet

A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet

Dysregulation of murine long non-coding single cell transcriptome in non-alcoholic steatohepatitis and liver fibrosis

Carbenoxolone mitigates extensive fibrosis formation in PLP-induced EAE model and multiple sclerosis serum-exposed pericyte culture

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