Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice.
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.
Oben
Jude A
JA
Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Roskams
Tania
T
Yang
Shiqi
S
Lin
Huizhi
H
Sinelli
Nicoletta
N
Li
Zhiping
Z
Torbenson
Michael
M
Thomas
Steven A
SA
Diehl
Anna Mae
AM
D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D004837:Epinephrine / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D020738:Leptin / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009638:Norepinephrine / Q000172:deficiency / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000322:Adrenergic Agonists; D020738:Leptin; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine; D004837:Epinephrine