Hedgehog/hyaluronic acid interaction network in nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma

Pazzaglia, Simonetta; Cifaldi, Loredana; Saran, Anna; Nobili, Valério; Fruci, Doriana; Alisi, Anna

doi:10.1002/hep.25783

Cited by 6 publications

(4 citation statements)

References 5 publications

(5 reference statements)

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“…Activation of the Hh pathway is a conserved feature of chronic liver disease, and NAFLD/NASH is no exception. Different rodent animal models of NAFLD show activation of the Hh pathway, demonstrated by increased expression of Hh ligands and Hh-producing cells, with accumulation of nuclear Gli-2 positive cells and increased expression of Gli-target genes such as osteopontin [ 42 , 53 , 61 , 62 , 63 , 64 , 65 ]. Furthermore, the activation of the Hh pathway is proportional to liver injury, namely to hepatocyte injury/apoptosis, ductular reaction and, most importantly, fibrosis [ 42 , 53 , 65 ].…”

Section: The Role Of Hedgehog In Animal Models Of Nashmentioning

confidence: 99%

Role of Hedgehog Signaling Pathway in NASH

Machado

Diehl

2016

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual’s response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

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Section: The Role Of Hedgehog In Animal Models Of Nashmentioning

confidence: 99%

Role of Hedgehog Signaling Pathway in NASH

Machado

Diehl

2016

IJMS

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“…Nevertheless, evaluations have recently indicated that Hh signalling can be reactivated during fibrosis or tissue remodelling [26–28]. Reactivation of Hh signalling has been demonstrated to happen in the lungs of patients with idiopathic pulmonary fibrosis [28], the fibrotic skin of scleroderma patients [30], animals with hyperoxic lung injury [29], animal models of liver fibrosis [32, 33] and human non-alcoholic fatty liver [31]. Sonic Hedgehog (SHH) ligand is upregulated in airway epithelial cells in lung fibrosis and Patched1 (Ptch1) expression is elevated in pulmonary interstitial cells [34].…”

Section: Introductionmentioning

confidence: 99%

Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression

Liu

Tang

et al. 2019

BMC Pulm Med

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BackgroundReactive oxygen species (ROS) levels largely determine pulmonary fibrosis. Antioxidants have been found to ameliorate lung fibrosis after long-term paraquat (PQ) exposure. The effects of antioxidants, however, on the signalling pathways involved in PQ-induced lung fibrosis have not yet been investigated sufficiently. Here, we examined the impacts of ligustrazin on lung fibrosis, in particular ROS-related autophagy and pro-fibrotic signalling pathways, using a murine model of PQ-induced lung fibrosis.MethodsWe explored the effects of microRNA-193 (miR-193a) on Hedgehog (Hh) and PI3K/Akt/mTOR signalling and oxidative stress in lung tissues. Levels of miR-193a, protein kinase B (Akt), phosphoinositide 3-Kinase (PI3K), ceclin1, mammalian target of rapamycin (mTOR), sonic hedgehog (SHH), myosin-like Bcl2 interacting protein (LC3), smoothened (Smo), and glioma-associated oncogene-1 (Gli-1) mRNAs were determined with quantitative real-time PCR. Protein levels of PI3K, p-mTOR, p-Akt, SHH, beclin1, gGli-1, LC3, smo, transforming growth factor-β1 (TGF-β1), mothers against DPP homologue-2 (Smad2), connective tissue growth factor (CTGF), collagen I, collagen III, α-smooth muscle actin (α-SMA) nuclear factor erythroid 2p45-related factor-2 (Nrf2), and p-Smad2 were detected by western blotting. In addition, α-SMA, malondialdehyde, ROS, superoxide dismutase (SOD), oxidised and reduced glutathione, hydroxyproline, and overall collagen levels were identified in lung tissues using immunohistochemistry.ResultsLong-term PQ exposure blocked miR-193a expression, reduced PI3K/Akt/mTOR signalling, increased oxidative stress, inhibited autophagy, increased Hh signalling, and facilitated the formation of pulmonary fibrosis. Ligustrazin blocked PI3K/Akt/mTOR and Hh signalling as well as reduced oxidative stress via increasing miR-193a expression and autophagy, all of which reduced pulmonary fibrosis. These effects of ligustrazin were accompanied by reduced TGF-β1, CTGF, and Collagen I and III expression.ConclusionsLigustrazin blocked PQ-induced PI3K/Akt/mTOR and Hh signalling by increasing miR-193a expression, thereby attenuating PQ-induced lung fibrosis.

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“…However, recent studies indicate that it may be reactivated in tissue remodeling or fibrosis (19)(20)(21). Reactivation of Hedgehog has been reported in lungs of patients with idiopathic pulmonary fibrosis (IPF) (21)(22)(23)(24)(25), in animals with hyperoxic lung injury (26), in fibrotic skin of patients with scleroderma (27), in human nonalcoholic fatty liver (28), and in animal models of liver fibrosis (29,30). Recent animal model studies suggest that Hedgehog signaling may play a role in fibrosis by promoting myofibroblast differentiation (27,31), but studies in human lung cells have not demonstrated such activity (23,24).…”

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confidence: 99%

Reemergence of Hedgehog Mediates Epithelial–Mesenchymal Crosstalk in Pulmonary Fibrosis

Liu

et al. 2015

Am J Respir Cell Mol Biol

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Hedgehog signaling plays important roles in cell development and differentiation. In this study, the ability of Sonic Hedgehog (SHH) to induce myofibroblast differentiation was analyzed in isolated human lung fibroblasts, and its in vivo significance was evaluated in rodent bleomycin-induced pulmonary fibrosis. The results showed that SHH could induce myofibroblast differentiation in human lung fibroblasts in a Smo- and Gli1-dependent manner. Gel shift analysis, chromatin immunoprecipitation assay, and site-directed mutagenesis revealed that a Gli1 binding consensus in the α-SMA gene promoter was important for mediating SHH-induced myofibroblast differentiation. Analysis of Hedgehog reemergence in vivo revealed that of all three Hedgehog isoforms, only SHH was significantly induced in bleomycin-injured lung along with Gli1. The induction of SHH was only noted in epithelial cells, and its expression was undetectable in lung fibroblasts or macrophages. transforming growth factor (TGF)-β induced SHH significantly in cultured alveolar epithelial cells, whereas SHH induced TGF-β in lung fibroblasts. Pulmonary fibrosis and α-smooth muscle actin (α-SMA) expression were significantly reduced in mice that were Smo deficient only in type I collagen-expressing cells. Thus, the reemergence of SHH in epithelial cells could result in induction of myofibroblast differentiation in a Smo-dependent manner and subsequent Gli1 activation of the α-SMA promoter.

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Hedgehog/hyaluronic acid interaction network in nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma

Cited by 6 publications

References 5 publications

Role of Hedgehog Signaling Pathway in NASH

Role of Hedgehog Signaling Pathway in NASH

Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression

Reemergence of Hedgehog Mediates Epithelial–Mesenchymal Crosstalk in Pulmonary Fibrosis

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