Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice

Biochem Biophys Res Commun. 2003 Aug 22;308(2):284-92. doi: 10.1016/s0006-291x(03)01360-3.


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 beta-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 alpha-adrenoceptor antagonist, inhibits this. Thus, leptin permits injury-related increases in adrenergic activity and requires NE to activate HSC and induce hepatic fibrogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic Agonists / pharmacology
  • Animals
  • Cell Count
  • Cells, Cultured
  • Collagen / genetics
  • Dopamine beta-Hydroxylase / deficiency
  • Dopamine beta-Hydroxylase / genetics
  • Epinephrine / physiology
  • Gene Expression / drug effects
  • Leptin / deficiency*
  • Leptin / genetics
  • Leptin / pharmacology
  • Leptin / physiology
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Norepinephrine / deficiency
  • Norepinephrine / pharmacology*
  • Norepinephrine / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sympathetic Nervous System / physiopathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta1


  • Adrenergic Agonists
  • Leptin
  • Tgfb1 protein, mouse
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen
  • Dopamine beta-Hydroxylase
  • Norepinephrine
  • Epinephrine