Morgan, ML;
Sigala, B;
Soeda, J;
Cordero, P;
Nguyen, V;
McKee, C;
Mouraliderane, A;
... Oben, JA; + view all
(2016)
Acetylcholine induces fibrogenic effects via M2/M3 ACh receptors in NASH and in primary human hepatic stellate cells.
Journal of Gastroenterology and Hepatology
, 31
(2)
pp. 475-483.
10.1111/jgh.13085.
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Abstract
BACKGROUND: The parasympathetic nervous system (PNS), via neurotransmitter Acetylcholine (ACh), modulates fibrogenesis in animal models. However, the role of ACh in human hepatic fibrogenesis is unclear. AIMS: We aimed to determine the fibrogenic responses of human hepatic stellate cells (hHSC) to ACh and the relevance of the PNS in hepatic fibrosis in patients with non-alcoholic steatohepatitis (NASH). METHODS: Primary hHSC were analysed for synthesis of endogenous ACh and acetylcholinesterase (AChE), and gene expression of choline acetyltransferase (ChAT) and muscarinic acetylcholine receptors (mAChR). Cell proliferation and fibrogenic markers were analysed in hHSC exposed to ACh, Atropine (Atrop), Mecamylamine (Mec), methoctramine and 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP). MAChR expression was analysed in human NASH scored for fibrosis. RESULTS: We observed that hHSC synthesise ACh and AChE, and express ChAT and M1-M5 mAChR. We also show that M2 was increased during NASH progression, while both M2 and M3 were found upregulated in activated hHSC. Furthermore, endogenous ACh is required for hHSC basal growth. Exogenous ACh resulted in hHSC hyperproliferation via mAChR and PI-3 K and MEK signalling pathways, as well as increased fibrogenic markers. CONCLUSION: We show that ACh regulates hHSC activation via M2 and M3 mAChR involving the PI-3 K and MEK pathways in vitro. Finally, we provide evidence that the PNS may be involved in human NASH fibrosis.
| Type: | Article |
|---|---|
| Title: | Acetylcholine induces fibrogenic effects via M2/M3 ACh receptors in NASH and in primary human hepatic stellate cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jgh.13085 |
| Publisher version: | http://dx.doi.org/10.1111/jgh.13085 |
| Language: | English |
| Additional information: | © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. This is the peer reviewed version of the following article: Morgan, ML; Sigala, B; Soeda, J; Cordero, P; Nguyen, V; McKee, C; Mouraliderane, A; (2016) Acetylcholine induces fibrogenic effects via M2/M3 ACh receptors in NASH and in primary human hepatic stellate cells. Journal of Gastroenterology and Hepatology , 31 (2) pp. 475-483, which has been published in final form at http://dx.doi.org/10.1111/jgh.13085. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. |
| Keywords: | Fibrosis; liver disease; parasympathetic nervous system |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1470370 |
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