Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors

Schumacher, Justin D.; Guo, Grace L.

doi:10.1155/2016/8323747

Cited by 58 publications

(56 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, we hypothesized that the mechanism by which FGF15 increases hepatic fibrogenesis is dependent upon reduction of BAs and inactivation of FXR. Additionally, given that other FGFs regulate HSC activation, we also hypothesized that FGF15 may function as a direct profibrotic stimulator to HSCs . These hypotheses were tested in both in vivo and in vitro models: (1) Cohorts of mice with various combinations of TBAP size and FGF15 expression were created by genetic and pharmacological means and then treated with CCl 4 ; (2) primary HSCs were isolated from WT and KO mice; and (3) the human HSC line, LX‐2, was treated with recombinant FGF19 with or without FXR‐activating BA.…”

Section: Discussionmentioning

confidence: 99%

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Schumacher

Kong

et al. 2019

Hepatology

Self Cite

View full text Add to dashboard Cite

Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15–/– mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15–/– mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4‐induced LF model in wild type (WT), Fgf15–/–, and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine‐ or cholic acid–containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15–/– mice; and (3) treatment of a human HSC line, LX‐2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15–/– mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15–/– mice. HSCs from Fgf15–/– mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX‐2 cells, FXR activation increased peroxisome proliferator‐activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c‐Jun N‐terminal kinase pathways and reduced nuclear factor kappa‐light‐chain‐enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Schumacher

Kong

et al. 2019

Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Fibrosis is a consequence of chronic injury associated with alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) as well as chronic viral diseases such as hepatitis C viral infection [3,4]. Hepatic stellate cells (HSCs) are the primary players in hepatic fibrosis development and progression [5]. When activated, HSCs transdifferentiate into α-smooth muscle actin (α-SMA) expressing myofibroblast-like cells, which are the major matrix-producing cells involved in hepatic fibrosis [1].…”

Section: Introductionmentioning

confidence: 99%

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

show abstract

“…Furthermore, we show that human FGF also stimulates proliferation and growth of mature metacestode vesicles. Both FGF1 and FGF2 are abundantly present in mammalian liver tissue where they are mostly released upon liver cell damage and during regeneration processes [17-20]. Although the precise amounts of host FGF in periparasitic lesions of E. multilocularis infected mice has not been measured to date, it is very likely that the early establishing metacestode is encountering considerable amounts of these cytokines since extensive damage to liver tissue is observed not only in chronically infected mice but also in early stages of the infection [4].…”

Section: Discussionmentioning

confidence: 99%

“…The stimulation of parasite development from stem cells towards mature metacestode vesicles by host FGF, as observed in our cultures, could thus help the parasite to abridge this critical phase and to successfully establish within the liver. Chronic AE is characterized by extensive liver fibrosis, particularly in the peri-parasitic area [57] and is thought to be mediated by hepatic stellate cells [5], which greatly upregulate FGF release during liver regeneration and fibrosis induction [20]. Hence, not only in the initial phase of parasite establishment, but also in the chronic phase of AE, the E. multilocularis metacestode should be in contact with elevated levels of host FGF that can continuously support parasite growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…FGFs have a key role in metazoan embryonic development and, in adults, are typically involved in regeneration processes (angiogenesis, wound healing, liver regeneration, regeneration of nervous tissue)[15]. In the liver, particularly FGF1 but also FGF2 are present as proteins in significant amounts [17], are crucially involved in tissue regeneration upon damage [18,19], and are also upregulated and released during fibrosis [20]. Secreted FGFs act through surface receptor tyrosine kinases of the FGF receptor family, of which four isoforms, Fgfr1-Fgfr4, are expressed by humans [15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

Förster

Koziol

Schäfer

et al. 2018

Preprint

View full text Add to dashboard Cite

22Background: Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode 23 larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-24 like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-25 failure. The molecular mechanisms of parasite organ tropism towards the liver and influences 26 of liver cytokines and hormones on parasite development are little studied to date. 27Methodology/Principal findings: We show that the E. multilocularis larval stage expresses 28 three members of the fibroblast growth factor (FGF) receptor family with homology to human 29 FGF receptors. Using the Xenopus expression system we demonstrate that all three 30 Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which 31 are present in the liver. In all three cases, activation could be prevented by addition of the 32 tyrosine kinase inhibitor BIBF 1120, which is used to treat human cancer. At physiological 33 concentrations, acidic and basic FGF significantly stimulated the formation of metacestode 34 vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the 35 parasite's mitogen activated protein kinase signalling system was stimulated upon addition of 36 human FGF. The survival of metacestode vesicles and parasite stem cells were drastically 37 affected in vitro in the presence of BIBF 1120. 38 Conclusions/Significance: Our data indicate that mammalian FGF, which is present in the 39 liver and upregulated during fibrosis, supports the establishment of the Echinococcus 40 metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling 41 system. These data are valuable for understanding molecular mechanisms of organ tropism 42 and host-parasite interaction in AE. Furthermore, our data indicate that the parasite's FGF 43 signalling systems are promising targets for the development of novel drugs against AE.44 3 45 Author summary 46 To ensure proper communication between their different cell populations, animals rely on 47 secreted hormones and cytokines that act on receptors of target cells. Most of the respective 48 cytokines, such as FGFs, evolved over 500 million years ago and are present in similar form 49 in all animals, including parasitic worms. The authors of this study show that the metacestode 50 larva of the tapeworm E. multilocularis, which grows like a malignant tumor within the host 51 liver, expresses molecules with homology to FGF receptors from mammals. The authors show 52 that human FGF, which is abundantly present in the liver, stimulates metacestode 53 development and that all parasite FGF receptors are activated by human FGF, despite 500 54 million years of evolutionary distance between both systems. This indicates that cells of the 55 Echinococcus metacestode can directly communicate with cells of the mammalian host using 56 evolutionarily conserved signaling molecules. This mode of host-pathogen interaction is 57 unique for helmint...

show abstract

Regulation of Hepatic Stellate Cells and Fibrogenesis by Fibroblast Growth Factors

Cited by 58 publications

References 58 publications

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

Contact Info

Product

Resources

About