Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice

Jude A. Oben, Tania Roskams, Shiqi Yang, Huizhi Lin, Nicoletta Sinelli, Zhiping Li, Michael Torbenson, Steven A. Thomas, Anna Mae Diehl

Research output: Contribution to journalArticle

Abstract

Leptin's actions on certain cells require a leptin-inducible neurotransmitter, norepinephrine (NE). NE modulates hepatic fibrosis. Therefore, decreased NE may explain why leptin deficiency inhibits hepatic fibrosis. We manipulated adrenergic activity in leptin-deficient ob/ob mice, leptin-sufficient, dopamine β-hydroxylase deficient (Dbh-/-) mice, and HSC cultures to determine if leptin requires NE to activate HSC and induce hepatic fibrosis. ob/ob mice have chronic liver injury, but reduced numbers of HSC. Supplemental leptin increases HSC, suggesting that leptin-dependent, injury-related factors permit expansion of HSC populations. NE also increases HSC numbers and activation, normalizing fibrogenesis. When fed hepatotoxic diets, NE-deficient Dbh-/- mice fail to accumulate activated HSC and have impaired fibrogenesis unless treated with adrenergic agonists. NE acts directly on HSC to modulate leptin's actions because leptin increases HSC proliferation and prazosin, an α-adrenoceptor antagonist, inhibits this. Thus, leptin permits injury-related increases in adrenergic activity and requires NE to activate HSC and induce hepatic fibrogenesis.

Original languageEnglish (US)
Pages (from-to)284-292
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume308
Issue number2
DOIs
StatePublished - Aug 22 2003

Keywords

  • Collagen
  • Fibrosis
  • Hepatic stellate cells
  • Norepinephrine
  • Ob/ob
  • Sympathetic nervous system
  • TGF-β

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Oben, J. A., Roskams, T., Yang, S., Lin, H., Sinelli, N., Li, Z., Torbenson, M., Thomas, S. A., & Diehl, A. M. (2003). Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice. Biochemical and Biophysical Research Communications, 308(2), 284-292. https://doi.org/10.1016/S0006-291X(03)01360-3