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Hepatic fibrogenesis requires sympathetic neurotransmitters.

Publication ,  Journal Article
Oben, JA; Roskams, T; Yang, S; Lin, H; Sinelli, N; Torbenson, M; Smedh, U; Moran, TH; Li, Z; Huang, J; Thomas, SA; Diehl, AM
Published in: Gut
March 2004

BACKGROUND AND AIMS: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative 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 alpha- and beta-adrenoceptor antagonists. HSC from dopamine beta-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 alpha-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor beta1 (TGF-beta1) 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-beta1 and collagen, and increased liver fibrosis. CONCLUSIONS: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis.

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Published In

Gut

DOI

ISSN

0017-5749

Publication Date

March 2004

Volume

53

Issue

3

Start / End Page

438 / 445

Location

England

Related Subject Headings

  • Sympathetic Nervous System
  • Receptors, Adrenergic
  • Rats, Sprague-Dawley
  • Rats
  • Norepinephrine
  • Neurotransmitter Agents
  • Mice, Obese
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

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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
Oben, J. A., T. Roskams, S. Yang, H. Lin, N. Sinelli, M. Torbenson, U. Smedh, et al. “Hepatic fibrogenesis requires sympathetic neurotransmitters.Gut 53, no. 3 (March 2004): 438–45. 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;53(3):438–45.
Oben, J. A., et al. “Hepatic fibrogenesis requires sympathetic neurotransmitters.Gut, vol. 53, no. 3, Mar. 2004, pp. 438–45. Pubmed, doi:10.1136/gut.2003.026658.
Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M, Smedh U, Moran TH, Li Z, Huang J, Thomas SA, Diehl AM. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004 Mar;53(3):438–445.

Published In

Gut

DOI

ISSN

0017-5749

Publication Date

March 2004

Volume

53

Issue

3

Start / End Page

438 / 445

Location

England

Related Subject Headings

  • Sympathetic Nervous System
  • Receptors, Adrenergic
  • Rats, Sprague-Dawley
  • Rats
  • Norepinephrine
  • Neurotransmitter Agents
  • Mice, Obese
  • Mice, Inbred C57BL
  • Mice
  • Male