Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Oben, JA; Roskams, T; Yang, S; Lin, H; Sinelli, N; Li, Z; Torbenson, M; Thomas, SA; Diehl, AM

Published Date

  • August 22, 2003

Published In

Volume / Issue

  • 308 / 2

Start / End Page

  • 284 - 292

PubMed ID

  • 12901866

Pubmed Central ID

  • 12901866

International Standard Serial Number (ISSN)

  • 0006-291X

Digital Object Identifier (DOI)

  • 10.1016/s0006-291x(03)01360-3

Language

  • eng

Conference Location

  • United States