Activated hepatic stellate cells: negative regulators of hepatocyte proliferation in liver diseases - PubMed (original) (raw)
Comment
Activated hepatic stellate cells: negative regulators of hepatocyte proliferation in liver diseases
Chuhan Chung et al. Hepatology. 2012 Jul.
Abstract
Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT2B) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT2B is clinically safe in humans and may be therapeutic in chronic liver disease.
Figures
Fig 1. Serotonin (5-HT) binds to its receptor 5-HT2B expressed in activated hepatic stellate cells (HSCs), produces transforming growth factor β1 (TGF-β1) in diseased livers and suppresses hepatocyte proliferation
In diseased livers, activated HSCs express a subclass of the 5-HT receptors, 5-HT2B. Serotonin binds to this receptor and activates ERK1 and 2, leading to an activation of transcription factor JunD to upregulate TGF-β1 expression. Since TGF-β1 is a powerful suppressor of hepatocyte proliferation, liver regeneration is inhibited by this mechanism. In contrast, in healthy livers, 5-HT promotes hepatocyte proliferation by directly binding to another subclass of the 5-HT receptors, 5-HT2A. Thus, 5-HT differentially regulates hepatocyte proliferation through its different receptors.
Comment on
- Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease.
Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, Ellis E, Lakey AF, Burt AD, Douglass A, Wright MC, White SA, Jaffré F, Maroteaux L, Mann DA. Ebrahimkhani MR, et al. Nat Med. 2011 Nov 27;17(12):1668-73. doi: 10.1038/nm.2490. Nat Med. 2011. PMID: 22120177 Free PMC article.
References
- Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J. 2008;411:1–18. - PubMed
- Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, Coleman N, et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology. 2005;128:33–42. - PubMed
- Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene. 2006;25:3818–3822. - PubMed
- Seuwen K, Pouyssegur J. Serotonin as a growth factor. Biochem Pharmacol. 1990;39:985–990. - PubMed
Publication types
LinkOut - more resources
Full Text Sources
Miscellaneous