Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice

• Published in: Biochemical and biophysical research communications Vol. 308; no. 2; pp. 284 - 292
• Main Authors: Oben, Jude A, Roskams, Tania, Yang, Shiqi, Lin, Huizhi, Sinelli, Nicoletta, Li, Zhiping, Torbenson, Michael, Thomas, Steven A, Diehl, Anna Mae
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22-08-2003
• Subjects: Adrenergic Agonists - pharmacology; Animals; Cell Count; Cells, Cultured; Collagen; Collagen - genetics; Dopamine beta-Hydroxylase - deficiency; Dopamine beta-Hydroxylase - genetics; Epinephrine - physiology; Fibrosis; Gene Expression - drug effects; Hepatic stellate cells; 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; Norepinephrine - deficiency; Norepinephrine - pharmacology; Norepinephrine - physiology; ob/ob; Rats; Rats, Sprague-Dawley; Sympathetic nervous system; Sympathetic Nervous System - physiopathology; TGF-β; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta1; ob/ob; Collagen; Fibrosis; Hepatic stellate cells; TGF-β; Norepinephrine; Sympathetic nervous system
• ISSN: 0006-291X; 1090-2104
• 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 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.