TITLE

Hepatic fibrogenesis requires sympathetic neurotransmitters

AUTHOR(S)
Oben, J. A.; Roskams, T.; Yang, S.; Lin, H.; Sinelli, N.; Torbenson, M.; Smedh, U.; Moran, T. H.; Li, Z.; Huang, J.; Thomas, S. A.; Diehl, A. M.
PUB. DATE
March 2004
SOURCE
Gut;Mar2004, Vol. 53 Issue 3, p438
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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 odrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylose 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 ore 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.
ACCESSION #
13492626

 

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