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Gene-Expression in Liver Cells in Health and Disease
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Gene-Expression in Liver Cells in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 9187

Special Issue Editor

Prof. Dr. Giuliano Ramadori

E-Mail Website
Guest Editor
Center of Internal Medicine, University Medical Center Goettingen, Robert-Koch Str. 38, D-37075 Goettingen, Germany
Interests: iron; cytokines; protein expression; liver
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver is the central “metabolic“ organ of the body. It is responsible for digestion, uptake, storage, and distribution of the nutrients introduced into the gastrointestinal tract.

The liver is also a central hematologic and endocrine organ. By controlling the production and elimination of blood cells(erythrocytes and granulocytes) and of the bulk of the serum proteins the liver is responsible for the formation and maintenance of the blood volume.

The liver is also a defense barrier against toxic and infectious agents.

The functional capacity of the liver increases after birth due to the increasing number of hepatocellular nuclei. The expression of different genes may be quantitatively different in the different zones of the liver. Under special circumstances, the size of hepatocytes located in the periportal area can also increase.

The liver is an important member of the defense system of the body. In the case of tissue damage at different sites, both hepatocytes and liver macrophages, directly and indirectly, participate in the clearance of the damaging noxae and of the tissue debris and in supporting the healing of the damaged tissue.

Such a perfectly functioning organ can be itself overwhelmed and damaged by toxins, most frequently by alcoholic beverages, xenobiotics, bacteria, viruses, and parasites. The persistence of damaging noxae leads to continuous damage without the chance to repair and, as a consequence, connective tissue replaces functioning cells.

Portal blood flow is then directed away from the sick liver. Physiologic and pathologic processes involve changes in the expression of groups of genes in each liver cell population.

Topics

  • Gene-expression studied at the transcriptional, post-transcriptional, and protein level in the cells, serum, and urine.
  • Liver gene-expression during embryonal and fetal development.
  • Liver gene-expression during early post-natal life
  • Gene-expression of the hepatic iron proteins.
  • Gene-expression of EPO
  • Gene-expression of different hormone receptors (steroid, thyroid, GH, insulin)
  • Gene-expression of chemokines
  • Gene-expression of cytokines
  • Gene-expression of acute-phase proteins
  • Gene-expression of the regeneration-process in different animal models.
  • HIF and related genes
  • Microbiota and liver gene expression.
  • Air pollution and liver gene expression
  • Changes in liver gene-expression induced by alcohol and by alcoholic beverages
  • Changes of liver gene-expression induced by cannabinoids

Prof. Dr. Giuliano Ramadori
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (3 papers)

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Research

10 pages, 1372 KiB  
Article
Hepatic IFNL4 Gene Activation in Hepatocellular Carcinoma Patients with Regard to Etiology
by Henriette Huschka and Sabine Mihm
Int. J. Mol. Sci. 2021, 22(15), 7803; https://doi.org/10.3390/ijms22157803 - 21 Jul 2021
Cited by 1 | Viewed by 1794
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is [...] Read more.
Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC. Full article
(This article belongs to the Special Issue Gene-Expression in Liver Cells in Health and Disease)
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17 pages, 3417 KiB  
Article
Single Cell Gene Expression Analysis in a 3D Microtissue Liver Model Reveals Cell Type-Specific Responses to Pro-Fibrotic TGF-β1 Stimulation
by Catherine Jane Messner, Lmar Babrak, Gaia Titolo, Michaela Caj, Enkelejda Miho and Laura Suter-Dick
Int. J. Mol. Sci. 2021, 22(9), 4372; https://doi.org/10.3390/ijms22094372 - 22 Apr 2021
Cited by 5 | Viewed by 4022
Abstract
3D cell culture systems are widely used to study disease mechanisms and therapeutic interventions. Multicellular liver microtissues (MTs) comprising HepaRG, hTERT-HSC and THP-1 maintain multicellular interactions and physiological properties required to mimic liver fibrosis. However, the inherent complexity of multicellular 3D-systems often hinders [...] Read more.
3D cell culture systems are widely used to study disease mechanisms and therapeutic interventions. Multicellular liver microtissues (MTs) comprising HepaRG, hTERT-HSC and THP-1 maintain multicellular interactions and physiological properties required to mimic liver fibrosis. However, the inherent complexity of multicellular 3D-systems often hinders the discrimination of cell type specific responses. Here, we aimed at applying single cell sequencing (scRNA-seq) to discern the molecular responses of cells involved in the development of fibrosis elicited by TGF-β1. To obtain single cell suspensions from the MTs, an enzymatic dissociation method was optimized. Isolated cells showed good viability, could be re-plated and cultured in 2D, and expressed specific markers determined by scRNA-seq, qRT-PCR, ELISA and immunostaining. The three cell populations were successfully clustered using supervised and unsupervised methods based on scRNA-seq data. TGF-β1 led to a fibrotic phenotype in the MTs, detected as decreased albumin and increased αSMA expression. Cell-type specific responses to the treatment were identified for each of the three cell types. They included HepaRG damage characterized by a decrease in cellular metabolism, prototypical inflammatory responses in THP-1s and extracellular matrix remodeling in hTERT-HSCs. Furthermore, we identified novel cell-specific putative fibrosis markers in hTERT-HSC (COL15A1), and THP-1 (ALOX5AP and LAPTM5). Full article
(This article belongs to the Special Issue Gene-Expression in Liver Cells in Health and Disease)
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14 pages, 3960 KiB  
Article
Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice
by Kamalakannan Radhakrishnan, Yong-Hoon Kim, Yoon Seok Jung, Jina Kim, Don-Kyu Kim, Sung Jin Cho, In-Kyu Lee, Steven Dooley, Chul-Ho Lee and Hueng-Sik Choi
Int. J. Mol. Sci. 2020, 21(19), 7148; https://doi.org/10.3390/ijms21197148 - 28 Sep 2020
Cited by 10 | Viewed by 2672
Abstract
Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, [...] Read more.
Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6. Full article
(This article belongs to the Special Issue Gene-Expression in Liver Cells in Health and Disease)
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