Hepatic fibrogenesis requires sympathetic neurotransmitters

J. A. Oben, T. Roskams, S. Yang, H. Lin, N. Sinelli, Michael Torbenson, U. Smedh, T. H. Moran, Z. Li, J. Huang, S. A. Thomas, A. M. Diehl

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferate fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylase deficient (Dbh-/-) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh-/- mice, as evidenced by reduced hepatic accumulation of α-smooth muscle actin+ve HSC and decreased induction of transforming growth factor β1 (TGF-β1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-β1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.

Original languageEnglish (US)
Pages (from-to)438-445
Number of pages8
JournalGut
Volume53
Issue number3
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

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Hepatic Stellate Cells
Neurotransmitter Agents
Liver
Norepinephrine
Sympathetic Nervous System
Adrenergic Receptors
Transforming Growth Factors
Wounds and Injuries
Fibrosis
Collagen
Phosphatidylinositol 3-Kinase
Myofibroblasts
Mixed Function Oxygenases
Leptin
Mitogens
Isoproterenol
GTP-Binding Proteins
Neuroglia
Liver Cirrhosis
Catecholamines

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Oben, J. A., Roskams, T., Yang, S., Lin, H., Sinelli, N., Torbenson, M., ... Diehl, A. M. (2004). Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut, 53(3), 438-445. https://doi.org/10.1136/gut.2003.026658

Hepatic fibrogenesis requires sympathetic neurotransmitters. / Oben, J. A.; Roskams, T.; Yang, S.; Lin, H.; Sinelli, N.; Torbenson, Michael; Smedh, U.; Moran, T. H.; Li, Z.; Huang, J.; Thomas, S. A.; Diehl, A. M.

In: Gut, Vol. 53, No. 3, 01.03.2004, p. 438-445.

Research output: Contribution to journalArticle

Oben, JA, Roskams, T, Yang, S, Lin, H, Sinelli, N, Torbenson, M, Smedh, U, Moran, TH, Li, Z, Huang, J, Thomas, SA & Diehl, AM 2004, 'Hepatic fibrogenesis requires sympathetic neurotransmitters', Gut, vol. 53, no. 3, pp. 438-445. https://doi.org/10.1136/gut.2003.026658
Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004 Mar 1;53(3):438-445. https://doi.org/10.1136/gut.2003.026658
Oben, J. A. ; Roskams, T. ; Yang, S. ; Lin, H. ; Sinelli, N. ; Torbenson, Michael ; Smedh, U. ; Moran, T. H. ; Li, Z. ; Huang, J. ; Thomas, S. A. ; Diehl, A. M. / Hepatic fibrogenesis requires sympathetic neurotransmitters. In: Gut. 2004 ; Vol. 53, No. 3. pp. 438-445.
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