TY - JOUR
T1 - Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice
AU - Oben, Jude A.
AU - Roskams, Tania
AU - Yang, Shiqi
AU - Lin, Huizhi
AU - Sinelli, Nicoletta
AU - Li, Zhiping
AU - Torbenson, Michael
AU - Thomas, Steven A.
AU - Diehl, Anna Mae
PY - 2003/8/22
Y1 - 2003/8/22
N2 - 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.
AB - 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.
KW - Collagen
KW - Fibrosis
KW - Hepatic stellate cells
KW - Norepinephrine
KW - Ob/ob
KW - Sympathetic nervous system
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=0043095414&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0043095414&partnerID=8YFLogxK
U2 - 10.1016/S0006-291X(03)01360-3
DO - 10.1016/S0006-291X(03)01360-3
M3 - Article
C2 - 12901866
AN - SCOPUS:0043095414
VL - 308
SP - 284
EP - 292
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -