Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

Le, Tao; Ma, Wenting; Wu, Lu; Xu, Ming-Yi; Yang, Yanqin; Zhang, Wei; Sha, Wenjun; Li, Hongshan; Xu, Jianrong; Feng, Rilu; Xue, Dongying; Zhang, Jie; Dooley, Steven; Seki, Ekihiro; Liu, Ping; Liu, Cheng

doi:10.1136/gutjnl-2018-317872

Cited by 46 publications

(31 citation statements)

References 41 publications

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“…These findings indicate that the SMAD3-SMAD4 signaling pathway is the downstream effector that mediates the increased expression of GDNF and furin by TGF-β1 in hGL cells. In human hepatic stellate cells, knockdown of SMAD2/3 abolishes the TGF-β-induced increase in GDNF [57]. In human liver cells (HepG2 cells), the expression of furin is induced and regulated by TGF-β1 via the MEK/p42/p44 MAPK and SMAD2-SMAD4 signaling pathways [38].…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells

Yin

Chang

et al. 2020

Cells

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Glial cell line-derived neurotrophic factor (GDNF) is expressed at a high level in the human ovary and GDNF signaling is involved in the direct control of follicular activation and oocyte maturation. Transforming growth factor-β1 (TGF-β1) plays an important role in the regulation of various ovarian functions. Furin is an intracellular serine endopeptidase of the subtilisin family that is closely associated with the activation of multiple protein precursors. Despite the important roles of GDNF and TGF-β1 in the regulation of follicular development, whether TGF-β is able to regulate the expression and production of GDNF in human granulosa cells remains to be determined. The aim of this study was to investigate the effect of TGF-β1 on the production of GDNF and its underlying mechanisms in human granulosa-lutein (hGL) cells. We used two types of hGL cells (primary hGL cells and an established immortalized hGL cell line, SVOG cells) as study models. Our results show that TGF-β1 significantly induced the expression of GDNF and furin, which, in turn, increased the production of mature GDNF. Using a dual inhibition approach combining RNA interference and kinase inhibitors against cell signaling components, we showed that the TβRII type II receptor and ALK5 type I receptor are the principal receptors that mediated TGF-β1-induced cellular activity in hGL cells. Additionally, Sma- and Mad-related protein (SMAD)3 and SMAD4 are the downstream signaling transducers that mediate the biological response induced by TGF-β1. Furthermore, furin is the main proprotein convertase that induces the production of GDNF. These findings provide additional regulatory mechanisms by which an intrafollicular factor influences the production of another growth factor through a paracrine or autocrine interaction in hGL cells.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells

Yin

Chang

et al. 2020

Cells

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“…Regardless, it is possible that GDNF functions as a trophic factor for hepatic neurons as well as executing direct effects on hepatic parenchymal and possibly non-parenchymal cells. Tao et al analyzed human liver tissue specimens and primary cell lines from human livers, and showed that GDNF is likely present in human HSCs as it is colocalized with α-smooth muscle actin positive cells (21).…”

Section: Glial Cell-line Derived Neurotrophic Factor and Non-alcoholimentioning

confidence: 99%

“…Similar results were seen in mouse fibrosis models. GDNF expression in the liver was increased by 2-4-folds in mice which received bile duct ligation or were fed with methionine-choline deficient diet, and by almost 13-fold in mice treated with CCl 4 (21). Whether the increase in GDNF plays a protective or exacerbating role in the pathogenesis of hepatic fibrosis remains elusive, and results are conflicting.…”

Section: Glial Cell-line Derived Neurotrophic Factor and Hepatic Fibrmentioning

confidence: 99%

“…Consequently, various neurotrophic factors have been explored as therapeutic agents in treatment of neurological disorders (17,18). Several neurotrophic factors and their receptors are expressed in various hepatic cell types (19)(20)(21), and regulate insulin sensitivity, lipid homeostasis, cellular injury and fibrosis of the liver (22)(23)(24)(25)(26). However, their potential in management of liver diseases including NAFLD remains mostly unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease

Amir

et al. 2020

Front. Med.

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Non-alcoholic fatty liver disease represents a continuum of excessive hepatic steatosis, inflammation and fibrosis. It is a growing epidemic in the United States of America and worldwide. Progression of non-alcoholic fatty liver disease can lead to morbidity and mortality due to complications such as cirrhosis or hepatocellular carcinoma. Pathogenesis of non-alcoholic fatty liver disease is centered on increased hepatic lipogenesis and decreased hepatic lipolysis in the setting of hepatic and systemic insulin resistance. Adipose tissue and hepatic inflammation can further perpetuate the severity of illness. Currently there are no approved therapies for non-alcoholic fatty liver disease. Most of the drugs being explored for non-alcoholic fatty liver disease focus on classical pathogenic pathways surrounding hepatic lipid accumulation, inflammation or fibrosis. Studies have demonstrated that the autonomic nervous system innervating the liver plays a crucial role in regulation of hepatic lipid homeostasis, inflammation and fibrosis. Additionally, there is growing evidence that neurotrophic factors can modulate all stages of non-alcoholic fatty liver disease. Both the autonomic nervous system and neurotrophic factors are altered in patients and murine models of non-alcoholic fatty liver disease. In this review we focus on the pathophysiological role of the autonomic nervous system and neurotrophic factors that could be potential targets for novel therapeutic approaches to treat non-alcoholic fatty liver disease.

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“…Also, the use of the CRISPR/Cas9 site-specific nuclease system has revolutionized the therapeutic options for several diseases, and may also provide new opportunities for the treatment of liver fibrosis. A recent study showing the antifibrotic effects of the knock down of the glial cell line-derived neurotrophic factor (GDNF) using the CRISPR/CAs9 in an adeno-viral delivery system [85] illustrates an exciting development.…”

Section: Drugs To Be Targetedmentioning

confidence: 99%

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

Poelstra

2020

Curr. Tissue Microenviron. Rep.

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Purpose of Review Treatment of liver fibrosis benefits from hepatic stellate cell (HSC)-specific delivery. Since the description of first carrier to HSC, many developments have taken place in this area. The purpose is to give an overview of the different carriers and homing moieties that are available for HSC targeting and illustrate the opportunities and hurdles they provide. Recent Findings There is a growing number of homing devices to deliver drugs to HSC, and options to deliver siRNA to HSC have emerged. Other developments include controlling corona formation, development of linker technology, and design of theranostic approaches. We are on the eve of reaching the clinic with innovative HSC-specific compounds. Summary An overview of different core molecules is presented together with an overview of targeting strategies toward different receptors on HSC, providing a versatile toolbox. Many therapeutics, ranging from small chemical entities and proteins to RNAor DNA-modulating substances, have already been incorporated in these constructs in the recent years.

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Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

Cited by 46 publications

References 41 publications

TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells

TGF-β1 Increases GDNF Production by Upregulating the Expression of GDNF and Furin in Human Granulosa-Lutein Cells

Hepatic Autonomic Nervous System and Neurotrophic Factors Regulate the Pathogenesis and Progression of Non-alcoholic Fatty Liver Disease

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

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