Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells
| Autor: | J Soeda, Chad McKee, Tania Roskams, Jude A. Oben, A Mouralidarane, Maelle Morgan, Ching-I Lin |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Liver Cirrhosis
Nicotine medicine.medical_specialty Biophysics Gene Expression Alpha (ethology) Nicotinic Antagonists Mecamylamine Receptors Nicotinic Pharmacology Biochemistry Transforming Growth Factor beta1 Phosphatidylinositol 3-Kinases Internal medicine Hepatic Stellate Cells medicine Humans Receptor Molecular Biology Cells Cultured Protein Kinase C Cell Proliferation Acetylcholine receptor biology Chemistry Smoking Cell Biology Transforming growth factor beta Nicotinic agonist Endocrinology biology.protein Hepatic stellate cell Collagen medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 417:17-22 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2011.10.151 |
| Popis: | Highlights: Black-Right-Pointing-Pointer Cigarette smoke may induce liver fibrosis via nicotine receptors. Black-Right-Pointing-Pointer Nicotine induces proliferation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Nicotine activates hepatic fibrogenic pathways. Black-Right-Pointing-Pointer Nicotine receptor antagonists attenuate HSC proliferation. Black-Right-Pointing-Pointer Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-{alpha}2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-{beta}1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type ({alpha}1, {beta}1, delta and epsilon) and neuronal type ({alpha}3, {alpha}6, {alpha}7, {beta}2 and {beta}4) nAChRmore » subunits at the mRNA level. Among these subunits, {alpha}3, {alpha}7, {beta}1 and {epsilon} were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-{alpha}2 and TGF-{beta}1 mRNA expression were significantly upregulated by nicotine and inhibited by mecamylamine. {alpha}1 and {alpha}3-nAChR mRNA expression was significantly upregulated in NASH fibrosis compared to normal livers. Conclusion: Nicotine at levels in smokers' blood is pro-fibrogenic, through actions on hHSCs expressed nAChRs. Therefore, CS, via its nicotine content, may worsen liver fibrosis. Moreover, nicotinic receptor antagonists may have utility as novel anti-fibrotic agents.« less |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect