A Role for Serotonin (5-HT) in Hepatic Stellate Cell Function and Liver Fibrosis

Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influenc...

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Bibliographic Details
Published in:	The American journal of pathology Vol. 169; no. 3; pp. 861 - 876
Main Authors:	Ruddell, Richard G., Oakley, Fiona, Hussain, Ziafat, Yeung, Irene, Bryan-Lluka, Lesley J., Ramm, Grant A., Mann, Derek A.
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Elsevier Inc 01-09-2006 ASIP American Society for Investigative Pathology
Subjects:	Animals Apoptosis - drug effects Biological and medical sciences Cell Proliferation - drug effects Cells, Cultured Drug Design Gastroenterology. Liver. Pancreas. Abdomen Humans Investigative techniques, diagnostic techniques (general aspects) Liver - injuries Liver - metabolism Liver - pathology Liver Cirrhosis - drug therapy Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Nerve Growth Factor - pharmacology Neurotransmitter Agents - pharmacology Other diseases. Semiology Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Rats Rats, Sprague-Dawley Receptors, Serotonin - metabolism Regular Serotonin - metabolism Serotonin Antagonists - pharmacology Serotonin Antagonists - therapeutic use Serotonin Plasma Membrane Transport Proteins - metabolism Hepatic fibrosis Kupffer cell Liver function Anatomic pathology Serotonin Neurotransmitter Digestive diseases Hepatic disease
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Summary:	Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influence HSC biology. Rat and human HSCs express the 5-HT 1B, 5-HT 1F 5-HT 2A 5-HT 2B, and 5-HT 7 receptors, with expression of 5-HT 1B 5-HT 2A and 5-HT 2B being induced on HSC activation. Induction of 5-HT 2A and 5-HT 2B was 106 ± 39- and 52 ± 8.5-fold that of quiescent cells, respectively. 5-HT 2B was strongly associated with fibrotic tissue in diseased rat liver. Treatment of HSCs with 5-HT 2 antagonists suppressed proliferation and elevated their rate of apoptosis; by contrast 5-HT was protective against nerve growth factor-induced apoptosis. 5-HT synergized with platelet-derived growth factor to stimulate increased HSC proliferation. HSCs were shown to express a functional serotonin transporter and to participate in both active uptake and release of 5-HT. We conclude that HSCs express key regulatory components of the 5-HT system enabling them to store and release 5-HT and to respond to the neurotransmitter in a profibrogenic manner. Antagonists that selectively target the 5-HT class of receptors may be exploited as antifibrotic drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0002-9440 1525-2191
DOI:	10.2353/ajpath.2006.050767