Roles of TGF-beta in hepatic fibrosis

Gressner, A. M.; Weiskirchen, Ralf; Breitkopf, Katja; Dooley, Steven

doi:10.2741/a812

Cited by 644 publications

(501 citation statements)

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“…STAT and SMAD pathways are known to be involved in the pathogenesis of liver fibrosis and inflammation, and elevated systemic and intrahepatic levels of IL-6 and TGF-␤ were found in acute and chronic liver diseases (30,31). The activation process of HSC, causing trans-differentiation of the physiologically quiescent cells to an activated myofibroblast-like cell type, is one of the key events of hepatic fibrosis.…”

Section: Resultsmentioning

confidence: 99%

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Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Bosserhoff¹,

Moser

Schölmerich

et al. 2003

Journal of Biological Chemistry

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The novel human gene MIA2 encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a GenBank TM search. MIA2, together with MIA, OTOR, and TANGO, belongs to the novel MIA gene family sharing important structural features, significant homology at both the nucleotide and protein levels, and similar genomic organization. In situ hybridization, reverse transcriptase-PCR, and Northern blots presented a highly tissue-specific MIA2 expression pattern in the liver. Promoter studies analyzing transcriptional regulation of MIA2 revealed an HNF-1-binding site at position ؊236 controlling hepatocyte-specific expression. Mutation of the site led to a complete loss of promoter activity in HepG2 cell. Further sites detected in the MIA2 promoter were consensus binding sites for SMAD and STAT3, Consistently, stimulation of MIA2 mRNA expression occurred by treatment with interleukin-6, transforming growth factor-␤, and conditioned medium from activated hepatic stellate cells. In accordance with these results, MIA2 mRNA was found to be increased in liver tissue of patients with chronic hepatitis C infection compared with controls. MIA2 mRNA levels were significantly higher in patients with severe fibrosis or inflammation than in patients with less severe fibrosis or inflammation. In summary our data indicate that MIA2 represents a potential novel acute phase protein and MIA2 expression responds to liver damage. The increased transcription in more severe chronic liver disease suggests that MIA2 may serve as a marker of hepatic disease activity and severity.

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Section: Resultsmentioning

confidence: 99%

“…TGF-␤ has pleiotropic functions including fibrinogenic action leading to trans-differentiation of HSC and negative regulation of proliferation and induction of apoptosis (31).…”

Section: Resultsmentioning

confidence: 99%

Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Bosserhoff¹,

Moser

Schölmerich

et al. 2003

Journal of Biological Chemistry

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“…In line, corresponding mouse models disrupted for the endoglin gene confirmed the importance of this receptor especially in TGF-␤ signaling (33)(34)(35)(36). Here, we have cloned the rat endoglin cDNA from HSC, the cell type that, upon TGF-␤ stimulation, is mainly responsible in liver for excessive formation of extracellular matrix components, resulting in hepatic fibrosis (55,71). In contrast to endothelial cells, expressing two endoglin transcript variants, denoted L-and S-endoglin, we found that rat HSC and MFB express two variants of L-endoglin most likely provoked by usage of different polyadenylation sites.…”

Section: Fig 9 Surface Exposition Of Endoglin In Hsc/mfbmentioning

confidence: 99%

“…Receptor Betaglycan-TGF-␤ is a growth factor regulating key aspects of cellular activation and transdifferentiation of HSC (55). The ligand, TGF-␤, is bound by a heterooligomeric membrane receptor complex, consisting of the signaling receptors type I and II and at least one accessory receptor betaglycan.…”

Section: Rat Hsc Express a Homolog Of Tgf-␤ Type III Familymentioning

confidence: 99%

Identification of Endoglin in Rat Hepatic Stellate Cells

Meurer

Tihaa

Lahme

et al. 2005

Journal of Biological Chemistry

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Transforming growth factor ␤ (TGF-␤) signaling is mediated by the cell surface TGF-␤ type I (ALK5), type II, and the accessory type III receptors endoglin and betaglycan. Hepatic stellate cells (HSC), the most profibrogenic cell type in the liver, express ALK5, T␤RII, and betaglycan. To monitor the expression of betaglycan in HSC, we used the commercially available antibody sc-6199 in Western blot analysis. This antibody, raised against a peptide mapping at the carboxyl terminus of the human betaglycan, is claimed to be specific for betaglycan, although it is known that the C-terminal domain is highly conserved in type III receptors. Proteins recognized in HSC by sc-6199 did not match the characteristic migration pattern of betaglycan. Moreover, the determined molecular weight (M r 160) and the observed reductant sensitivity after treatment with dithiothreitol resemble those of a closely related type III receptor, endoglin (CD105). Endoglin, a disulfide-linked homodimer, is an accessory component of the TGF-␤ receptor complex and mainly expressed on endothelial cells. The presence of endoglin in HSC of rat liver was confirmed by molecular cloning of the endoglin cDNA and immunocytochemistry. The reactivity of sc-6199 with both auxiliary TGF-␤ receptors (betaglycan and endoglin) from rats was demonstrated by Western blot and immunocytochemical analysis of cells heterologously expressing these proteins. Furthermore, Northern and Western blotting revealed that both betaglycan and endoglin genes are differentially regulated in HSC and in transdifferentiated myofibroblasts (MFB). By surface labeling and immunoprecipitation experiments, we show that endoglin is found in significant amounts exposed at the plasma membrane of HSC and MFB, which is a pivotal prerequisite for binding of and signaling in response to TGF-␤. In conclusion, we hypothesize that TGF-␤ signals in HSC and MFB are tuned by two different interconnected signaling pathways, as it was previously demonstrated for endothelial cells.The transforming growth factor family of growth factors regulates a diverse set of physiologic processes including proliferation, cellular differentiation, apoptosis, and expression of extracellular matrix genes (1-3). Signaling by the three identified mammalian TGF-␤ 1 isoforms TGF-␤1, TGF-␤2, and TGF-␤3 is initiated by binding to the high affinity cell surface receptors, the accessory TGF-␤ type III receptor (T␤RIII) (4), the type II receptor (T␤RII) (5), and type I (6) receptor (T␤RI), of which T␤RII and T␤RI possess intracellular serine/threonine kinase domains. Upon binding of TGF-␤1 or TGF-␤3 to the receptor type II, the liganded receptor dimer associates with and its constitutive active kinase transphosphorylates the type I receptor at the GS domain (7). The active type I receptor in turn phosphorylates and thereby activates the intracellular signal transducers represented by the R-Smad family members 2 and 3 (2, 7, 8).Because TGF-␤2 has a lower affinity for the type II receptor (9, 10), cells sense this ligand by eithe...

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“…Both, (TGF-β) excess and deficiency are causal for the development of fibrotic and autoimmune liver diseases respectively which can be inhibited by anti-(TGF-β) treatments like neutralizing antibodies. In the liver, (TGF-β) is a very potent profibrogenic mediator of cellular responses leading to tissue repair, ECM production, growth regulation, and apoptosis [12]. stages in cerebral blood flow and brain, and provides a way of increasing the Aβ-induced cellular stress underlying neuronal dysfunction and dementia ( Figure 3).…”

Section: Transforming Growth Factormentioning

confidence: 99%

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

Riaz¹,

Fazal-ur-Rehman²,

Ahmad³

2017

Med chem

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Abstractβ-amino acids are an important class of macromolecules. They play role in life for survival. β-amino acids gained significant interest due to their interesting pharmaceutical uses as hypoglycemic, antiketogenic characteristics, sterile and antifungal activities, anthelminthic as well as potent insecticidal characteristics. These are vital building blocks for the preparation of pharmaceutical and agrochemical target molecules. These are utilized in development of drugs, bimolecular structure and molecular recognition. They are also important in treatment of different diseases which are viral to human health. They play important role in regulation of nutritional metabolism and immunity. It has also led to their wider adoption as intermediates in new drugs and has been a focus of considerable attention in medicinal chemistry. β-amino acids have found extensive applications as components of biologically active peptides and small molecule pharmaceuticals. Synthetic derivatives of biologically relevant peptides incorporating β-amino acids often display interesting pharmacological activity, with increased potency and enzymatic stability. β-peptides participate in arrangement of incredible stable auxiliary structures. This review summarizes recent developments about the different roles of β-amino acids in human biology and some implications in medicinal chemistry.

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Roles of TGF-beta in hepatic fibrosis

Cited by 644 publications

References 142 publications

Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Identification of Endoglin in Rat Hepatic Stellate Cells

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

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